ISBN : 978-81-951800-6-6

A TEXT BOOK OF

PHARMACEUTICAL
REGULATORY SCIENCE
FOR B.PHARMACY FINAL YEAR
(As per PCI Syllabus)

Dr. B. E Wanjari, K. K. Khalode,

K. B. Bhendarkar, M. N. Rangari

Aditi Publication
Raipur, Chhattisgarh, India
www.shodhsamagam.com
 A TEXT BOOK OF
PHARMACEUTICAL REGULATORY SCIENCE
FOR
B.PHARMACY FINAL YEAR
(As per PCI Syllabus)

PHARMACEUTICAL
REGULATORY SCIENCE

Writer’s
Dr. B. E Wanjari K. K. Khalode
K. B. Bhendarkar M. N. Rangari

Publisher
Aditi Publication, Raipur, Chhattisgarh, INDIA
PHARMACEUTICAL REGULATORY SCIENCE

2021
Issue - 01, Volume - 01

Writer’s
Dr. Bhumeshkumar E. Wanjari
M. Pharm, Ph.D
Associate Professor
Krushnakumar D. Khalode
M.Pharm
Assistant Professor
Krishna B. Bhendarkar
M.pharm
Assistant Professor
Mithun N. Rangari
M. Pharm
Assistant Professor
Gondia College of Pharmacy, Gondia

ISBN : 978-81-951800-6-6

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 Preface

Regulatory Affairs is a comparatively new profession which has developed from the
desire of governments to protect public health, by controlling the safety and efficacy of prod-
ucts in areas including pharmaceuticals, veterinary medicines, medical devices, pesticides, agro-
chemical, cosmetics and complementary. In present edition, all the possible efforts has been
made to incorporate all the data available on pharmaceutical regulatory affairs science.

Very few books are available on this subject, the material in most of the books is pre-
sented in diffused form or is highly specialized and discernible to those proficient in the field.
The main objective of writing this book is to present the information as per the pharmacy
council of India syllabus designed for eights semester of B. Pharmacy.

This book consist of five units. Almost each unit contain one to two chapters. Chapter
one of unit one includes, New Drug Discovery and development. The unit two consist of two
chapters including Regulatory Approval Process and Regulatory authorities and agencies. Unit
three is Registration of Indian drug product in overseas market. Unit four consist of two chap-
ters Clinical trials and lastly unit 5 consist of one chapter Regulatory Concepts.

The constructive suggestion for further improvements from teachers and students are
welcome.

Gondia Dr. Bhumeshkumar E. Wanjari

Mr. Krushnakumar D. Khalode
Mr. Krishna B. Bhendarkar
Mr. Mithun N. Rangari
 Our Team

Dr. B.E. Wanjari is Principal&Associate Professor in Gondia College of

Pharmacy. Completed his Ph. D. from Dept. of Pharmaceutical sciences
RTMNU Nagpur and Master of Pharmacy in Pharmaceutics from RGUHS
Banglore. He has 16 years of experience in teaching and 31 publi cati ons
i n Internat ional J ournal, 1 publi cati on i n Nati onal J ournal .

K ru s h na k u m a r D. K ha l o de i s A s s i s t a nt P r of e s s o r, De p a r t m e n t o f
Pharmaceutical Chemistry in Gondia College of Pharmacy. He has done his
Master of Pharmacy in Pharmaceutical chemistry from R. T. M. N.U. and
pursuing his Ph. D. from SPV university. He has two years of Industrial
Experience and five years of Experience in Teaching and has 20 publications.

K. R. Bhendarkar is Assistant Professor, Department of Pharmaceutical

Quality Assurance in Gondia College of Pharmacy. He has completed his
Master of Pharmacy from R. T. M. N. U. University. He has 8 years of
Experience in Marketing and has 3 years of Experience in Teaching and has
6 publications.

M . N. Rangari is Assistant Professor, Department of Pharmaceutical

Chemistry in Gondia College of Pharmacy. He has done his Master in
Pharmaceutical Chemistry from R. T. M. N.U. University. He has 4 years of
experience in teaching and has 8 publications.
 C ONTENTS
Unit Chapter Contents P.No.
Unit III Chapter 1 01-20
New Drug Discovery and development
Stages of drug discovery
Drug development process
Pre-clinical studies
Non-clinical activities
Clinical studies
Innovator and generics
Concept of generics
Generic drug product development.
Unit II Chapter 1 21-67

Regulatory Approval Process

Approval processes and time-lines involved in Investigational-
New Drug (IND)
New Drug Application (NDA)
Abbreviated New Drug Application (ANDA
Changes to an approved NDA / ANDA
Chapter 2 68-77
Regulatory authorities and agencies
Overview of regulatory authorities of (Organization structure
and types of applications):
India
United States
European Union
Australia
Japan
Canada
Unit III Chapter 1 78-95
Registration of Indian drug product in overseas market
Procedure for export of pharmaceutical products
Technical documentation, Drug Master Files (DMF)
Common Technical Document (CTD)
Electronic Common Technical 163 Document (eCTD)
ASEAN Common Technical Document (ACTD)research
Unit Chapter Contents P.No.
Unit IV Chapter 1 096-136
Clinical trials
Developing clinical trial protocols
Institutional Review Board / Independent Ethics committee –
formation and working procedures
Informed consent process and procedures
GCP obligations of Investigators
Sponsors & Monitors
Managing and Monitoring clinical trials
Pharmacovigilance - safety monitoring in clinical trials
Unit V Chapter 1 137-166
Regulatory Concepts
Basic terminology
Guidance
Guidelines
Regulations
Orange Book
Federal Register
Code of federal regulatory
Purple book
 UNIT - I

CHAPTER 01

New Drug Discovery and development

Stages of drug discovery

Drug development process

Pre-clinical studies

Non-clinical activities

Clinical studies

Innovator and generics

Concept of generics

Generic drug product development.

dfdf
 New Drug Discovery and
01 developmes of drug discovery
Background
Drug discovery is multifaceted process which involved identification of a drug chemicals to find
out therapeutic use in treating and management of various disease conditions.
The drug discovery process of drug includes identification of drug candidates, synthesis,
characterization, screening, and assays for therapeutic efficacy. When a molecule avails its satisfactory
results in these investigations, it will commence the process of drug development subsequent to clinical
trials. Drug discovery and development is an expensive process due to the high budgets of R&D and
clinical trials. It takes almost 12-15 years to develop a single new drug molecule from the time it is
discovered when it is available in market for treating patients. The average cost for research and
development for each efficacious drug is likely to be $900 million to $2 billion. This figure includes
the cost of the thousands of failures: For every 5,000-10,000 compounds that enter the investigation
and development pipeline, ultimately only one attains approval. These statistics challenge imagination,
but a brief understanding of the R&D process can explain why so many compounds don‘t make it and
why it takes such a large, lengthy effort to get one medicine to patients. The Success requires immense
resources the best scientific and logical minds, highly sophisticated laboratory and technology; and
multifaceted project management. It also takes persistence and good fortune. Eventually, the process
of drug discovery brings hope, faith and relief to billions of patients.
Stages of Drug Discovery and Development Process
Across the pharmaceutical industry there are several mandated processes that must be undergone
before the final sale of a drug can begin on the market. Following are the different stages which are
required to get approval of new drug for market authorization from Food and Drug Administration
(FDA).
1. Targetidentification
2. Targetvalidation
3. lead identification
4. lead optimization
5. Product characterization
6. Formulation and development
7. Pre- clinical research
8. Investigational New Drug
9. Clinicaltrials
10. New Drug Application & Approval

1
 Figure 1: Stages of drug discovery and development process
1. Target Identification
Every year thousands of molecule discover through high- throughput screening which leads to
identify target. By interaction with target, potential drug is assessed. Lead compounds are further
screened after assessment and then screened for their properties and activities to develop safe and
effective medicine.
The first step in the discovery of a drug is identification of the biological origin of a disease, and
the potential targets for intervention. Target identification starts with isolating the function of a possible

2
therapeutic target (gene/nucleic acid/protein) and its role in the disease. [6] Identification of the target is
followed by characterization of the molecular mechanisms addressed by the target. An ideal target
should be efficacious, safe, meet clinical and commercial requirements and be druggable‘. The
techniques used for target identification may be based on principles of molecular biology, biochemistry,
genetics, biophysics, or other disciplines.

Figure 2: Target Identification

Approaches
i. Data mining using bio-informatics
ii. Identifying, selecting and prioritizing potential disease targets
iii. Genetic association
iv. Genetic polymorphism and connection with the disease
v. Expression profile
vi. Changes in mRNA/protein levels
vii. Pathway and phenotypic analysis- In vitro cell-based mechanistic studies
viii. Functional screening
ix. knockdown, knockout or using target specific tools
2. Target Validation
Target validation is the process by which the expected molecular target – for example gene,
protein or nucleic acid of a small molecule is certified. Target validation includes: determining the
structure activity relationship (SAR) of analogs of the small molecule; generating a drug-resistant
mutant of the presumed target; knockdown or over expression of the presumed target; and monitoring
the known signaling systems downstream of the presumed target.
Target validation is the process of demonstrating the functional role of the identified target in the
disease phenotype. Whilst the validation of a drug‘s efficacy and toxicity in numerous disease-relevant
cell models and animal models is extremely valuable – the ultimate test is whether the drug works in
a clinical setting.

3
 Figure 3 : Target Validation
Target validation can be broken down in to two key steps.
i. Reproducibility
Once a drug target is identified, whether it be via a specific technique or from review of literature,
the first step is to repeat the experiment to confirm that it can be successfully reproduced. The target
validation technique includes affinity chromatography, expression-cloning, protein micro-array, reverse
transected cell micro-array, biochemical suppression, siRNA, DNA micro-array, system biology and
study of existing drugs.
ii. Introduce variation to the ligand (drug)-target- environment
Genetic manipulation of target genes (in vitro) knocking down the gene (shRNA, siRNA, miRNA),
knocking out the gene (CRISPR), knocking in the genes (viral transfection of mutant genes) Antibodies,
interacting to the target with high affinity and blocking further interactions, Chemical genomics, chemical
approaches against genome encoding protein.
3. Identification of Lead
A chemical lead is defined as a synthetically stable, feasible, and drug like molecule active in
primary and secondary assays with acceptable specificity, affinity and selectivity for the target receptor.
This requires definition of the structure activity relationship as well as determination of synthetic
feasibility and preliminary evidence of in vivo efficacy and target engagement. It is also called as
developmental candidate. Characteristics of a chemical lead are:
i. SARdefined
ii. Drug ability (preliminary toxicity, hERG)
iii. Synthetic feasibility
iv. Select mechanistic assays
v. In vitro assessment of drug resistance and efflux potential
vi. Evidence of in vivo efficacy of chemical class
vii. PK/Toxicity of chemical class known based on preliminary toxicity or in silico studies
In order to decrease the number of compounds that fail in the drug development process, a drug
ability assessment is often conducted. This assessment is important in transforming a compound from
a lead molecule into a drug. For a compound to be considered druggable it should have the potential to
bind to a specific target; however, also important is the compound‘s pharmacokinetic profile regarding
absorption, distribution, metabolism, and excretion. Other assays will evaluate the potential toxicity
of the compound in screens such as the Ames test and cytotoxicity assay.

4
 Figure 4 : Lead Identification
4. Lead Optimization
Lead optimization is the process by which a drug candidate is designed after an initial lead
compound is identified. The process involves iterative series of synthesis and characterization of a
potential drug to build up a representation of in what way chemical structure and activity are related in
terms of interactions with its targets and its metabolism.

Figure 5 : Lead Optimization

In initial drug discovery, the resulting leads from hit-to-lead high throughput screening tests
undergo lead optimization, to identify promising compounds. Potential leads are evaluated for a range
of properties, including selectivity and binding mechanisms during lead optimization, as the final step
in early stage drug discovery. The purpose of lead optimization is to maintain favorable properties in
lead compounds, while improving on deficiencies in lead structure. In order to produce a pre-clinical
drug candidate, the chemical structures of lead compounds (small molecules or biologics) need to be
altered to improve target specificity and selectivity. Pharmacodynamic and pharmacokinetic parameters
and toxicological properties are also evaluated. Labs must acquire data on the toxicity, efficacy, stability

5
and bio-availability of leads, in order to accurately characterize the compound and establish the route
of optimization.
Researchers in drug discovery need rapid methods to narrow down the selection of drug candidates
for this downstream selectivity profiling and further investigation. High throughput DMPK (drug
metabolism and pharmacokinetics) screens have become an essential part of lead optimization,
facilitating the understanding and prediction of in vivo pharmacokinetics using in vitro tests. In order
to make new drugs with higher potency and safety profiles, chemical modifications to the structure of
candidate drugs are made through optimization. Automated screening systems are becoming an important
part of pharmaceutical and bio-pharmaceutical drug discovery labs. Mass spectrometry is used for the
detection and quantitation of metabolites. MALDI imaging is a key technique for evaluating drug
candidates and their metabolites in tissue structure rapidly and accurately. Additionally, NMR Fragment-
based Screening (FBS) in the pharmaceutical industry has become a widely applied method for the
discovery and optimization of lead molecules in targeted screening campaigns.
5. Product Characterization
When any new drug molecule shows a promising therapeutic activity, then the molecule is
characterized by its size, shape, strength, weakness, use, toxicity, and biological activity. Early stages
of pharmacological studies are helpful to characterize the mechanism of action of the compound.
6. Formulation and Development
Pharmaceutical formulation is a stage of drug development during which the physicochemical
properties of active pharmaceutical ingredients (APIs) are characterized to produce a bio-available,
stable and optimal dosage form for a specific administration route.
During pre-formulation studies the following parameters are evaluated:
 Solubility in different media and solvents
 Dissolution of the active pharmaceutical ingredient(API)
 Accelerated Stability Services under various conditions
 Solid state properties (polymorphs, particle size, particle shape etc.)
 Formulation services and capabilities
 Formulation development of new chemical entities(NCE)
 Optimization of existing formulations
 Process development for selected dosage forms
 Novel formulations for improved delivery of existing dosage forms
 Controlled release and sustained release formulations
 Self-emulsifying drug delivery systems
 Colloidal drug delivery systems
 Sub-micron and nano-emulsions
7. Pre- clinical Testing
Pre-clinical research in drug development process involves evaluation of drug‘s safety and efficacy
in animal species that conclude to prospective human outcome. The pre- clinical trials also have to
acquire approval by corresponding regulatory authorities. The regulatory authorities must ensure that
trials are conducted in safe and ethical way and would give approval for only those drugs which are
confirm to be safe and effective. ICH has established a basic guideline for technical necessities of
acceptable preclinical drug development.
6
The pre-clinical trials can be conducted in two ways: General pharmacology and Toxicology.
Pharmacology deals with the pharmacokinetic and pharma codynamic parameters of drug. It is essential
to explore unwanted pharmacological effects in suitable animal models and monitoring them in
toxicological studies. Pharmacokinetic studies are very important to make known the safety and efficacy
parameters in terms of absorption, distribution, metabolism and excretion. These studies give information
on absorption rate for diverse routes of administration, which helps in selection of dosage form,
distribution, rate of metabolism and elimination; which governs the half-life of the drug. Half-life of
the drug clarifies the safety outline of the drug which is the obligatory for a drug to get approved by
regulatory agencies. The drug distribution mechanism elucidates the therapeutic effectiveness of the
drug as it depends on the drugs bio-availability and its affinity. Drug metabolism provides the probability
of through phases of bio-transformation process and formation of drug metabolites. It also helps in
understanding the reactions as well as enzymes involved in bio-transformation.
Toxicological studies of the drug can be performed by in- vitro and in-vivo test which evaluate
the toxicological effects of the drug. In-vitro studies can be performed to inspect the direct effects on
cell proliferation and phenotype. In-vivo studies can be performed for qualitative and quantitative
determination of toxicological effects. As many drugs are species specific, it is essential to select
appropriate animal species for toxicity study. In-vivo studies to evaluate pharmacological and
toxicological actions, including mode of action, are often used to support the basis of the proposed use
of the product in clinical studies.
8. The Investigational New Drug Process (IND)
Drug developers must file an Investigational New Drug application to FDA before commencement
clinical research. In the IND application, developers must include:
 Preclinical and toxicity study data
 Drug manufacturing information
 Clinical research protocols for studies to be conducted
 Previous clinical research data (if any)
 Information about the investigator/developer
9. Clinical Research
Clinical trials are conducted in people (volunteer) and intended to answer specific questions
about the safety and efficacy of drugs, vaccines, other therapies, or new methods of using current
treatments. Clinical trials follow a specific study protocol that is designed by the researcher or
investigator or manufacturer. As the developers design the clinical study, they will consider what they
want to complete for each of the different Clinical Research Phases and starts the Investigational New
Drug Process (IND), a process they must go through before clinical research begins. Before a clinical
trial begins, researchers review prior information about the drug to develop research questions and
objectives. Then, they decide:
Selection criteria for participants
Number of people take part of the study
Duration of study
Dose and route of administration of dosage form
Assessment of parameters
Data collection and analysis

7
 Figure 6 : Phases of clinical trials
i. Phase 0- clinical trial
Implicates investigative, first-in-human (FIH) trials that are conducted according to FDA
guidelines. Phase 0 trials besides termed as human micro dose studies, they have single sub-therapeutic
doses given to 10 to 15 volunteers and give pharmacokinetic data or help with imaging specific targets
without exerting pharmacological actions. Pharmaceutical industries perform Phase 0 studies to pick
which of their drug applicants has the preeminent pharmacokinetic parameters in humans.
ii. Phase 1- Safety and dosage
Phase I trials are the first tests of a drug with a lesser number of healthy human volunteers. In
most cases, 20 to 80 healthy volunteers with the disease/condition participate in Phase 1. Patients are
generally only used if the mechanism of action of a drug indicates that it will not be tolerated in healthy
people. However, if a new drug is proposed for use in diabetes patients, researchers conduct Phase 1
trials in patients with that type of diabetes. Phase 1 studies are closely monitored and collect information
about Pharma codynemics in the human body. Researchers adjust dosage regimen based on animal
study data to find out what dose of a drug can tolerate the body and what are its acute side effects. As
a Phase 1 trial continues, researchers find out research mechanism of action, the side effects
accompanying with increase in dosage, and information about effectiveness. This is imperative to the
design of Phase 2 studies. Almost 70% of drugs travel to the next phase.
iii. Phase 2- Efficacy and side effects
Phase II trials are conducted on larger groups of patients (few hundreds) and are aimed to evaluate
the efficacy of the drug and to endure the Phase I safety assessments. These trials aren‘t sufficient to
confirm whether the drug will be therapeutic. Phase 2 studies provide with additional safety data to the
researchers. Researchers use these data to refine research questions, develop research methods, and
design new Phase 3 research protocols. Around 33% of drugs travel to the next phase.
8
 Most prominently, Phase II clinical studies aid to found therapeutic doses for the large-scale
Phase III studies.
iv. Phase 3- Efficacy and adverse drug reactions monitoring
Researchers plan Phase 3 studies to prove whether a product deals an action benefit to a specific
people or not. Sometimes known as pivotal studies, these studies comprise 300 to 3,000 volunteers.
Phase 3 studies deliver most of the safety data. The previous study might not able to detect less common
side effects. But phase 3 studies are conducted on large no. of volunteers and longer in duration, the
results are more probable to detect long-term or uncommon side effects. Around 25-30% of drugs
travel to the next phase of clinical research.
If a drug developer has data from its previous tests, preclinical and clinical trials that a drug is
safe and effective for its intended use, then the industry can file an application to market the medicine.
The FDA review team comprehensively inspects all submitted data on the drug and makes a conclusion
to approve or not to approve it. New Drug Application
A New Drug Application (NDA) expresses the full story of a drug molecule. Its purpose is to
verify that a drug is safe and effective for its proposed use in the people studied. A drug developer must
include all about a drug starting from pre- clinical data to Phase 3 trial data in the NDA. Developers
must include reports on all studies, data, and analysis. Beside with clinical trial outcomes, developers
must include:
 Proposed labeling
 Safety updates
 Drug abuse information
 Patent information Institutional review board compliance information
 Directions for use
v. FDA Review
Once FDA obtains a complete NDA then FDA team of review may require about 6 to 10 months
to take a pronouncement on whether to approve the NDA. If Once FDA obtains an incomplete NDA
then FDA team of review refuse the NDA.
If FDA governs that a drug has been revealed to be safe and effective for its proposed use, it is
then essential to work with the developer for upgrade prescribing information. This is
denotedas¯ labeling. Labeling precisely defines the basis for approval and direction how to use the
drug. Although, remaining issues required to be fixed before the drug to be approved for marketing. In
other cases, FDA have need of additional studies. At this situation, the developer can choose whether
to continue further development or not. If a developer distresses with an FDA decision, there are tools
for official appeal.
vi. Phase 4- Post-Market Drug Safety Monitoring
Phase 4 trials are conducted when the drug or device has been approved by FDA. These trials are
also recognized as post- marketing surveillance involving pharmacovigilance and continuing technical
support after approval. There are numerous observational strategies and assessment patterns used in
Phase 4trials to evaluate the efficacy, cost- effectiveness, and safety of an involvement in real-world
settings. Phase IV studies may be required by regulatory authorities (e.g. change in labelling, risk
management/minimization action plan) or may be undertaken by the sponsoring company for
competitive purposes or other reasons. Therefore, the true illustration of a drug ‘s safety essentially
requires over the months and even years that mark up a drug ‘s lifespan in the market. FDA reviews
reports of complications with prescription and OTC drugs, and can decide to add precautions to the
dosage or practice information, as well as other events for more serious adverse drug reactions.
9
10. A New Drug Application and Approval
A new drug application (NDA) is a comprehensive document that must be submitted to the
U.S. Food and Drug Administration (FDA) in order to request approval for marketing a new drug in
the United States.
The new drug approval is of two phase process - the first phase for clinical trials and second
phase for marketing authorization of drug. Firstly, non-clinical studies of a drug are completed to
ensure efficacy and safety, and then application for conduct of clinical trials is submitted to the competent
authority of the concerned country. Thereafter, the clinical trials can be conducted (phase I to phase
IV). These studies are performed to ensure the efficacy, safety and optimizing the dose of drug in
human beings. After the completion of clinical studies of the drug, then an application to the competent
authority of the concerned country for the approval of drug for marketing is submitted. The competent
authority review the application and approve the drug for marketing only if the drug is found to be safe
and effective in human being or the drug have more desirable effect as compare to the adverse effect .
Even after the approval of new drug, government should monitor its safety due to appearance of
some side effects, when it is used in larger population. The interactions with other drugs, which were
not assessed in a pre-marketing research trial and its adverse effects (in particular populations), should
also be monitored.
Innovator and Generics
Drug
Any substance or pharmaceutical product for human use that is intended to modify or explore
physiological systems or pathological states for the benefit of the recipient
Innovator product
The innovator product is generally that which was first authorized for marketing (normally as a
patented product)
When a substance has been available for many years, it may not be possible to identify an
innovator pharmaceutical product
Generic drug
A pharmaceutical product, usually intended to be interchangeable with the innovator product,
marketed after expiry of the patent or other exclusivity rights.
Generic products may be marketed either under the approved nonproprietary name or under a
brand (proprietary) name.
They may be marketed in dosage forms and/or strengths different from those of the innovator
products
Concept of Generics and Generic Drug Product Development
Definitions of Generics
Confusion often surrounds terms used in the global field of generics and biosimilars.
The source of some of this confusion is due to authorities in various regions of the world defining
terms differently and other instances due to a misunderstanding of the actual nature, characteristics,
and method of research and manufacture of generic and biological products.
In an attempt to improve public understanding and avoid confusion, GaBI Online has decided to
provide tables of definitions used in different countries or regions. Table 1 shows a glossary of the
relevant terms for biosimilars as defined by WHO.

10
WHO Definitions Relevant to Generics
Active pharmaceutical ingredient (API)
The chemical substance responsible for a product’s effect. In this manual, it is called ‘substance’.
Bioequivalence
Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their
bioavailabilities (rate and extent of availability), after administration in the same molar dose,
are similar to such a degree that their effects can be expected to be essentially the same.
Brand name
Name given to a pharmaceutical product by the manufacturer, e.g. Valium is the originator brand
name (also called trade name) for diazepam. The use of this name is reserved exclusively to its
owner as opposed to the generic name, i.e. diazepam. Brand names may also be used for generic
products; they are then often called ‘branded generics. These brand names are different from
innovator brand names. See generic medicine.
Comparator
The term ‘comparator’ is used to mean ‘the pharmaceutical product with which the new product
is intended to be interchangeable in clinical practice’. In any particular market, the comparator
should be the first in this list that is available:
 The product for which efficacy, safety and quality have been fully established (often the innovator)
 A market leader that has been authorized for marketing after a process of assessment a market
leader that is legally marketed but has not been assessed prior to marketing authorization.
Dispensing fee
Normally a fixed fee that pharmacies are allowed to charge per prescribed item instead of, or in
addition to a percentage mark-up. The fee more accurately reflects the work involved in dispensing
a prescription; a percentage mark-up makes profit dependent on the sale of expensive medicines.
Dosage form
The administration form of the completed pharmaceutical product, e.g. tablet, capsule, suspension,
injection. Also called ‘dose form’ or ‘dosing unit’
Drug
Any dosage form containing a substance approved for the prevention and treatment of disease.
The term ‘medicine’ is increasingly used to distinguish it from a drug as a substance that is
misused. See also Pharmaceutical product
Essential medicines
Essential medicines are intended to be available within the context of functioning health systems
at all times, in adequate quantities, in the appropriate dosage forms, with assured quality and
adequate information, and at a price the individual and community can afford. The WHO model
list of essential medicines is intended to be flexible and adaptable to many different situations;
the precise definition of the medicines that are regarded as essential remains a national
responsibility.
Excipient
Any component of a finished dosage form other than the claimed therapeutic ingredient or
ingredients.
Finished product
A product that has undergone all stages of production, including packaging in its final container
and labelling.
11
 Formulatio
The composition of a dosage form, including the characteristics of its raw materials and the
operations required to process it.
Generic medicine/ Multi-source product
A pharmaceutical product usually intended to be interchangeable with the originator brand product,
manufactured without a license from the originator manufacturer and marketed after the expiry
of patent or other exclusivity rights.
Generic medicines are marketed either under a non-proprietary name, for example diazepam or
occasionally another approved name, rather than under a proprietary or brand name. However, they are
also quite frequently marketed under brand names, often called ‘branded generics. Many different
branded generic products of the same medicine can be on the market in a country along with the
originator brand product.
The manual ‘Marketing Authorization of Pharmaceutical Products with Special Reference to
Multi-source (Generic) Products (WHO/DMP/RGS/98.5)’ defines and uses the term ‘multi-source
pharmaceutical product’ for generic products. This includes even an originator brand for which the
patent has expired. This definition of a generic is used in some countries, but the manual distinguishes
between originator brand, regardless of its patent status, and lowest-priced generic equivalents.
Innovator brand
International non-proprietary name (INN)
A common, generic name selected by designated experts for the unambiguous identification of a
new pharmaceutical substance. The selection process is based on a procedure and guiding principles
adopted by the World Health Assembly. INNs are recommended for worldwide use.
The system was introduced by WHO in 1950 as a means of identifying each pharmaceutical
substance or active pharmaceutical ingredient by a unique name that is universally accessible as public
property (non-proprietary). It is often identical to the generic name, e.g. diazepam. A brand name
(trade name) should not be derived from the INN name.
Interchangeable pharmaceutical products
Products within a therapeutic class but with different active ingredients are interchangeable if
they have equivalent therapeutic effect.
Medicine
Any dosage form containing a substance approved for the prevention and treatment of disease.
The term ‘medicine’ is increasingly used to distinguish it from a drug as a substance that is misused.
See also Pharmaceutical product
Originator pharmaceutical product/originator brand
Generally the product that was first authorized worldwide for marketing, normally as a patented
product, on the basis of the documentation of its efficacy, safety and quality, according to requirements
at the time of authorization, e.g. Valium. The originator product always has a brand name; this name
may, however, vary between countries.
Some substances (e.g. prednisolone and isoniazid) are so old that no originator can be identified
and the patent was probably never claimed.
Patent
A title granted by public authorities that confers a temporary monopoly for the exploitation of an
invention upon the person who reveals it, furnishes a sufficiently clear and full description of it, and
claims this monopoly.
12
Patient co-payments
Payments by patients of a fixed amount per prescribed medicine, even if reimbursed.
Pharmaceutical equivalence
Medicines with identical amounts of the same active ingredient in the same dosage form and
route of administration that meet the standards of strength, quality, purity and identity.
Pharmaceutical product
Any medicine intended for human use, presented in its finished dosage form that is subject to
control by pharmaceutical legislation (registered). A product may be sold under a brand name (e.g.
Valium) or under the generic name (e.g. diazepam).
Substance
See active pharmaceutical ingredient.
Stability
The ability of an active ingredient or a drug product to retain its properties within specified
limits throughout its shelf life. The chemical, physical, microbiological and bio-pharmaceutical aspects
of stability must be considered.
Trade name
See brand name.

Generic Drug Product Development

Background
The drug which have same chemical composition as branded drug and sold under there chemical
name is known as generic drug. Generic drug marketed when a patient and exclusivity protection of
research product is ended and when patent owner waives its rights or the requirement of FDA are met.
The FDA aspires to continually improve its pre- application interactions with applicants. To
facilitate these interactions and to keep stakeholders as informed as possible, the agency provides the
following resources and guidance on developing generic drug products and preparing and submitting
abbreviated new drug applications (ANDAs).
i. Product-Specific Guidance for Generic Drug Development
To facilitate generic drug product availability and to assist the generic pharmaceutical industry
with identifying the most appropriate methodology for developing drugs and generating evidence
needed to support ANDA approval, FDA regularly publishes product-specific guidance’s describing
the Agency’s current thinking and expectations on how to develop therapeutic equivalents to specific
reference listed drugs.
ii. Generic Drug Approvals
FDA regularly updates a listing of first generic drug approvals. To view all generic drug approvals
and tentative approvals, use the “Drug Approval Reports by Month” feature on Drugs FDA and select
“Original Abbreviated New Drug Approvals (ANDAs) by Month” for generic drug approvals or
“Tentative Approvals by Month” for tentative approvals. The database is updated daily.
iii. Pre-ANDA Program
The Pre-ANDA Program is a valuable information resource for generic drug applicants. The
program features product development assistance and pre-submission and mid-review cycle meetings
to help clarify regulatory expectations early in product development and during application review.

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 i. List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic
The FDA maintains a list of approved new drug application (NDA) drug products that are no
longer protected by patents or exclusivities, and for which the FDA has not approved an ANDA
referencing that NDA drug product.
ii. Authorized Generic Drugs
The FDA List of Authorized Generic Drugs, updated quarterly, includes the drug trade name,
the brand company manufacturer, and the date the authorized generic drug entered the market.
iii. Quality by Design (QbD)
QbD is a scientific, risk-based, proactive approach to pharmaceutical development, incorporating
deliberate design effort and appreciating how processes impact product performance. FDA has
published two QbD report examples:
a. Inactive Ingredient Database
The Inactive Ingredient Database provides information on inactive ingredients present in FDA-
approved drug products, and can be used as an aid in developing generic drug products.
b. Hatch-Waxman Letters
The FDA has posted certain letters reflecting FDA’s decisions on 180-day exclusivity and other
matters related to generic drug approvals.
iv. FDA Letters to Industry
This series of letters informs generic drug product manufacturers of policy and procedure
developments with respect to the Drug Price Competition and Patent Term Restoration Act of
1984.
v. Bioequivalence Study Retention Samples
The FDA provides requirements for retaining samples of drug products used in bio-availability
and bioequivalence testing. Regulations state that applicants shall retain reserve samples of the
tested products administered to study subjects and release these samples to FDA upon request.
Educational Resources
The FDA Center for Drug Evaluation and Research Small Business & Industry Assistance program
offers a variety of multimedia learning resources. The CDER SBIA Learn web page has many helpful
courses and recordings in the “Generic Drugs” section.
Process of generic product development
The process of generic product development firs needs the physical development of any product
which will require a formulator to:
Choose from the same types of available excipients.
Choose from the same types of available processes.
Utilize similar types of equipment, in similar types of facilities, meeting similar regulations.
Some people still truly believe that generic products are inferior top brand name products.
However, the facts are:
Generic products must meet the same quality standards as brand name products. The efficacy of
generic products vs. the designated reference product must be proven through the use of a bio equivalency
study. The facilities and procedures used to manufacture generic products must meet the same cGMP
requirements as brand name products. Admittedly, there can be both good product development and
poor product development practices in either brand name or generic pharmaceutical companies.
Fortunately stricter regulatory and process validation requirements have helped to weed out poorly

14
developed products making the proper development of robust formulations more essential than ever.
Although this information primarily concerns solid oral dosage forms, many of the general principles
discussed here would be applicable to generic semi-solid or liquid products as well.
Prior to Development
A product for development must be selected. In order to properly select a product, input is
needed from a variety of disciplines including:
- R&D
- Regulatory Affairs
- Legal
- Marketing & Sales
- Finance, etc.
Once selected, details of the selected product should be recorded into some kind of document to
include information such as:
- Innovator Product Description and Dosage Form
- Innovator Product Packaging Description
- Innovator Product Sales
- Generic Product Description and Dosage Form
- Generic Product Packaging Description
- Generic Sales Forecasts
- Intended Manufacturing Site
- Intended Production Batch Size
- Any other relevant information
Based on patent expiry, product exclusivity, forecasts, availability of the active ingredient etc.,
the project needs to be scheduled and its’ progress tracked and managed with the goal of being the first
generic drug manufacturer (for that particular product) on the market.
Pre-formulation
Prior to preparing actual trial formulations, “pre-formulation” work must be performed to obtain
as much information about the reference product and drug substance as possible.
Common pre-formulation activities include the following:
Review of the product selection document
Review of any pertinent patent information
Obtain samples of reference product and packaging
Evaluate physical characteristics of the reference product
Determine reference drug release characteristics through “in-vitro” dissolution profiling.
Characterize drug substance to determine drug form (i.e. crystalline, powder, amorphous), drug
solubility, polymorphism, particle size, bulk density, flow characteristics, chemistry (i.e. pKa, functional
groups), drug absorption characteristics (pharmacokinetics), incompatibilities, sensitivities (light, heat,
moisture), etc.
Identify a discriminating dissolution procedure with relevant in-vitro/in-vivo correlations.
Following these “pre-formulation” activities, decisions can be made as to the type of formulation
and process to be considered for development. (Dosage form and dosage strength are determined by
the reference product itself, and by the requirements detailed in the product selection document.)

15
There are three general processes used to produce tablets and capsules, as follows:
Direct Mix
This process involves simply blending the drug substance with excipients and compressing the
mixture into tablets or filling it into capsule shells.
Dry Granulation
This process involves processing the drug substance with excipients using a “slugging” or
“compaction” technique followed by “granulation sizing” and final blending with additional excipients
prior to tablet compression, or capsule shell filling.
Wet Granulation
This process involves processing the drug substance with excipients and a solvent in which a
binder may be dissolved to produce a granulation. The granulation is subsequently dried, sized and
blended with additional excipients prior to tablet compression or capsule shell filling.
Whenever possible or practical, a direct mixing process is initially considered since this process
usually offers the simplest and most economical means to produce a solid pharmaceutical dosage
form. However, the product dosage, physical drug characteristics, and even characteristics of the
reference product itself, will ultimately determine what type of process is feasible.
A tablet or capsule dosage form will generally contain the following components:
Active Ingredient- Drug substance
Binder- Holds filler and drug particles together in agglomerates to form granules or tablets or
capsule slugs, etc.
Solvent- Used in “wet granulations” as the granulating medium
Fillers/Diluents- Used to provide bulk or weight to tablets and capsules to make tablets or
capsules of a practical size for administration
Disintegrating Agent- Used to cause granules and/or tablets and/or capsule contents to break
apart to enhance the availability of drug substance for dissolution and absorption
Glidant- Used to reduce inter-particulate friction thereby improving flow characteristics
Anti-adherent- Similar role as lubricant, but more specialized for effectiveness at preventing
adhesion to equipment surfaces. (Should be used in combination with a lubricant.)
Lubricant- Used to prevent sticking of powders to equipment used to compress tablets or fill
capsule shells (i.e. tablet punches and dies, encapsulating dosators or tamping pins).
Others
Dyes-Impart a colour to the tablet
Sweetening Agents & Flavours- Used in chewable tablets.
Wetting Agents- Used to enhance drug substance ‘wetting’ and solubility.
Acidifying Agents, Buffers, Stabilizers, Etc.- Excipients added to provide a more stable
environment for the drug substance involved.
Film Coating Preparations- If a tablet is to be film-coated, the components of the material used
for coating will include a polymeric film-former, a plasticizer, and may or may not include, an opacifying
agent, a dispersing agent, one or more dyes, etc.
It is impossible to list every conceivable example or potential use for the large number of excipients
available to fulfill the various roles as components of tablet and capsule formulations.

16
 Therefore, only some of the most common excipients and their suggested use levels are listed as
follows:
Binders:
Polyvinylpyrrolidone (PVP)-0.5-5%
Pregelatinized starch - 5-10% (wet), 5-20% (direct)
Starch paste- 5-25% w/w
Microcrystalline cellulose - 5-25% (wet), 5-25% (direct)
Sucrose- 50-70% solution
Hydroxypropyl cellulose- 4-6%
Ethylcellulose- 5% solution
Methylcellulose- 1-5% solution (depending on viscosity grade)
Acacia- 1-5%
Solvents:
Purified water
Ethanol
Purified water/ethanol
Other organic solvents (i.e. Methylene Chloride)
Fillers/Diluents:
Microcrystalline cellulose
Lactose
Starch/pregelatinized starch
Dicalcium phosphate
Calcium carbonate
Compressible sugars
Mannitol
Sorbitol
Disintegrating Agents:
Sodium starch glycolate- 4-8%
Croscarmellose sodium- 3-6%
Pregelatinized starch- 5-10%
Starch- 5-10%
Microcrystalline cellulose- 5-15%
Cross-linked polyvinylpyrrolidone- 2-5%
Alginic Acid- 5-10%
Glidants/Lubricants/Antiadherents:
Fumed silicon dioxide (glidant)-0.1-0.5% (anti-adherent)-1-2%
Talc (anti-adherent)- 1-4%
Magnesium stearate- 0.25-1.5%
Stearic acid- 0.5-3%
Hydrogenated vegetable oils- 2-5%
Sodium lauryl sulfate- 1-3%
Mineral oil- 1-3%

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Others:
Dyes- Usually aluminum lakes: water soluble dyes precipitated with the hydrous oxide of
aluminum.
Sweetening Agents & Flavours- Compressible sugars/alcohols & various flavouring agent
Wetting Agents- Sodium lauryl sulfate- 0.1-2%,
Polysorbate 80- 0.1-3%
Acidifying Agents, Buffers, Stabilizers, etc.-
Citric acid- 0.3-2%
Sodium citrate- 0.3-2%(dihydrate)
Sodium phosphate monobasic
Considerations for Selecting Excipients in a Formulation
Composition of Reference Product (if available)- PDR, CPS or product labels will often list
qualitative composition o formulations.
Requirement for Specific Excipient
Formulations should start out simple, with additional, specialized excipients being incorporated
as needed through experimental trials.
Drug/Excipient Incompatibilities
Drug characterization and pre-formulation studies may exclude specific excipients due to potential
incompatibility or stability issues.
Excipient Characteristics/Affect on Drug Substance Release
Depending on the drug substance, certain excipients may be selected due to their affect at
enhancing or retarding the release of the drug substance to produce the desired “in-vitro” dissolution
release profile.
Formulation Process
Certain excipients are specialized for direct mixing processes whereas others are more suitable for wet
granulation processes.
Availability
Excipients most readily available are usually selected over excipients that may be equally adequate,
but not readily available.
Experience
Formulators usually select excipients with which they have the most experience, even though
there may be equivalent excipients to perform the same function.
Cost
With two functionally equivalent, equally available excipients, the cheaper of the two may be
selected.
Formulation Development
Once pre-formulation work and a development strategy are completed, a series of small-scale
trials are prepared. These trials involve processing the drug substance with excipients using the selected
process to produce a dosage form with the desired strength and appearance dictated in the product
selection document. The dosage form is then physically and chemically evaluated to determine its
acceptability relative to the reference product.

18
The following represents the common types of testing performed on tablet and capsule formulations
under development:
Blends
Physical Testing: Bulk and tapped density, particle size distribution, flow index, angle of repose,
moisture and/or L.O.D.
Chemical Testing: Blend uniformity
Tablets
Physical Testing: Appearance, average weight and weight variation, hardness, thickness, friability,
disintegration time
Chemical Testing: Dissolution profiles vs. reference product, assay, content uniformity, chemical
identification, impurities and related substances, ICH stability
Capsules
Physical Testing: Appearance, average weight and weight variation, disintegration time
Chemical Testing: Dissolution profiles vs. reference product, assay, content uniformity, chemical
identification, impurities and related substance, ICH Stability
Development trials continue until a formulation with a matching dissolution profile, relative to
the reference product, is obtained in one or more dissolution media.
This formulation should then be scaled-up to a slightly larger size and the resulting dosage form
packaged, and placed on accelerated stability stations for monitoring. In the meantime, additional
trials should be prepared to optimize various formulation and process parameters.
These optimization trials are very important and serve to:
Provide experience with the new formulation and process.
Determine limitations by challenging various process parameters
Provide additional data necessary for setting meaningful specifications
Identify significant formulation or processing issues that can be addressed before the product
formulation and process is “locked” (i.e. prior to bioequivalency testing)
If the product retains acceptable physical and chemical characteristics, it is further scaled-up
under GMP conditions to serve as the “test batch” for “in-vivo bioequivalency testing” vs. the reference
product. If the product proves to be “non-bioequivalent” to the reference product, reformulation is
required, assuming that the continued development of this product remains economically viable due
to this delay.
If the product proves to be “bioequivalent” to the reference product, a submission package is
assembled and submitted to the respective Government Regulatory Agency for review and eventual
approval.
The key to a successfully developed generic product goes beyond a successful bioequivalency
study, product approval, and a successful process validation study. A truly successful generic product
is a product that can be made repeatedly, by any trained operator, on any qualified piece of equipment,
at any time of the year, without any problems. The complete procedure for generic drug development
is depicted in figure 7.

19
Figure 7 : Generic Drug Product Development

20
 UNIT - II

CHAPTER 01
Regulatory Approval Process

Approval processes and time-lines involved in

Investigational New Drug (IND)

New Drug Application (NDA)

Abbreviated New Drug Application (ANDA

Changes to an approved NDA / ANDA

CHAPTER 02
Regulatory authorities and agencies

Overview of regulatory authorities of

(Organization structure and types of
applications):
India
United States
European Union
Australia
Japan
Canada
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dfd

20
 01 Regulatory Approval Process

Background
A regulatory process, by which a person/ organization/ sponsor/ innovator gets authorization
to launch a drug in the market, is known as drug approval process. In general, a drug approval
process comprises of various stages: application to conduct clinical trials, conducting clinical
trials, application to marketing authorization of drug and post-marketing studies. Every country
has its own regulatory authority, which is responsible to enforce the rules and regulations and
issue the guidelines to regulate the marketing of the drugs.
Investigational Product
ICH GCP defines an investigational product as,
“A pharmaceutical form of an active ingredient or place bobeingtested or used a sa reference
in a clinical trial”(ICHGCP1.33).
This may include a marketed product that is being used in a different form than the one it
was approved for, or a marketed product being used for an unapproved or new indication.
Definition of an Investigational New Drug
The Code of Federal Regulations (CFR) defines an investigational new drug as: “A new
drug or biological drug that is used in a clinical investigation.”
In the U.S. Food and Drug Administration (FDA) regulations, an investigational new drug
is any substance (suchasadrug, vaccine or other biological product) for which FDA approval is
being sought.

Investigational New Drug Application

Background
An Investigational New Drug Application (IND) is a request for authorization from the Food
and Drug Administration (FDA) to administer an investigational drug or biological product to
humans.
An investigational new drug is a new drug or biological drug that is used in a clinical
investigation. This term also includes biological products used in vitro for diagnostic purposes.
The Investigational New Drug Application (IND) is a request for an exemption from the federal
statute that prohibits an unapproved drug from being shipped in interstate commerce.
IND is not an application for marketing authorization of a drug. For the purpose of this
lesson, “IND” is synonymous with “Notice of Claimed Investigational Exemption for a New
Drug.”Upon completion of preclinical study and collection of data, the sponsor (the person who
takes responsibility for and initiates a clinical investigation) must submit an application to FDA
to notify FDA it is conducting a clinical study on human subjects.
This application is called an Investigational New Drug Application (INDA or IND).
Investigational new drug application abbreviated as INDA is a mandatory requirement filed with
the FDA in order to seek permission for administering a new drug under investigation to Human
subjects after completion of the preclinical studies on it.
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 It confers protection to the subjects and also sees that the investigational plan is efficient
and designed to achieve its required objectives.
The sponsor of the drug is responsible for the initiation of clinical trials.
He might be an individual i.e. sponsor-investigator, a pharmaceutical company, governmental
agency, academic institution or private or public organization.
The INDA is filed with the FDA under Title 21, Code of Federal Regulations Section 312-
the guidelines for preapproval of all clinical testing’s are specified.
Content of Investigational New Drug Application
1. All the requirements for submitting an INDA are prescribed in the Code of Federal
Regulations and are submitted under a cover sheet (Form FDA- 1571).
2. The items required are:
i. Name, address and telephone number of the sponsor of the drug.
ii. Name and title of the person responsible for monitoring the conduct and progress of
the investigation.
iii. Names and titles of the persons responsible for the review and evaluation of information
relevant to the safety of the drug.
iv. Name and address of any contract research organization involved in the study (if any).
v. Identification of the phase/phases of clinical investigation to be conducted.
vi. Introductory statement and general investigational plan including, name of drug and
all active ingredients, structural formula and pharmacological class, formulation, route
of administration, and broad objectives and planned duration of study.
vii. Description of the investigational plan.
3. The reason for selecting a drug or research study. Indications to be studied, approach to
evaluation of the drug, types of studies, estimated number of subjects to be given the drug, and
any risks anticipated based on animal studies.
i. Brief summary of previous experience with the drug, including reasons if the drug is
withdrawn.

22
 ii. Chemistry and manufacturing control information like physical, chemical and biologic
characteristics, product stability during the clinical investigation.
iii. Pharmacological and Toxicological information.
iv. If the drug is a combination of previously investigated components, then preclinical
and clinical data of these components when given singly and in combination.
v. Clinical protocol for planned study.
vi. Commitment that an “Institutional Review Board” (IRB) has approved the study and
will continue to monitor the investigation.
vii. Investigators brochure.
viii. Commitment not to begin clinical investigations until IND is in effect signature of the
sponsor or authorized representative and the date of signed application.
4. After submission of IND to the FDA, it is assigned to the various divisions of Center for
Drug Research and Evaluation wing of the FDA for its review and evaluation.
5. The FDA has 30days from the receipt of IND to decide whether the proposed clinical trial
should proceed or not. If the sponsor is not contacted within 30days, the trial may proceed.
6. Meanwhile reviewers at FDA may put a “Clinical Hold” on the proposed Clinical trials at
any time. This prevents human testing of drug. It may be due to the following reasons
i. If there is any unreasoned threat to the safety of the trial subjects i.e. if the subjects
face any illness or injury due to treatment.
ii. Insufficient data to assess patient risks.
iii. If the investigators involved in the study do not meet the necessary requirements with
respect their qualification.
iv. Misleading or incomplete investigators brochure.
7. In case if all the requirements for FDA approval are satisfied an IND is granted. Once an
IND is in effect, all the proposed changes to the original IND thereafter, must be submitted as
amendments for approval.
Requirements of IND Application
The FDA imposes substantial requirements and conditions on therapeutic drug products,
including lengthy and detailed laboratory and clinical testing procedures, sampling activities, and
other costly and time-consuming processes. After preclinical testing, as required by the applicable
regulations, an Investigational New Drug (IND) application must be filed with the FDA to obtain
authorization for human testing through clinical trials. This application includes a description of
the overall plan for investigating the drug product and a comprehensive protocol for planned
studies. Pursuant to the regulations, the FDA usually asks companies to submit a description of
the drug substance, including its physical, chemical, and biological characteristics, as well as a
description of the general method of preparation of the drug substance and a list of all components,
including inactive ingredients. A section of the IND describes the composition, manufacture, and
control of the drug substance. The drug company must provide sufficient information to assure
the proper identification, quality, purity, and strength of the investigational drug. The IND should
also contain adequate information about pharmacological and toxicological studies of the drug,
involving laboratory animals and other tests on the basis of which the sponsor has concluded that
it is reasonably safe to conduct the proposed clinical trials. Where there has been widespread use
of the drug outside of the U.S., it is possible in some limited circumstances to submit a well-
23
documented clinical experience as part of the required preclinical work. Once the FDA approves
the IND, the sponsor is allowed to enter the clinic where certain reporting requirements, such as
making progress reports on the study or studies covered by the IND, must be met and the sponsor
must alert the FDA and clinical investigators immediately of any unforeseen serious side effects
or injuries.
Approval processes and time-lines involved in Investigational New Drug
(IND)
Current Federal law requires that a drug be the subject of an approved marketing application
before it is transported or distributed across state lines. Because a sponsor will probably want to
ship the investigational drug to clinical investigators in many states, it must seek an exemption
from that legal requirement. The IND is the means through which the sponsor technically obtains
this exemption from the FDA.
During a new drug’s early preclinical development, the sponsor’s primary goal is to determine
if the product is reasonably safe for initial use in humans, and if the compound exhibits
pharmacological activity that justifies commercial development. When a product is identified as
a viable candidate for further development, the sponsor then focuses on collecting the data and
information necessary to establish that the product will not expose humans to unreasonable risks
when used in limited, early-stage clinical studies.
FDA’s role in the development of a new drug begins when the drug’s sponsor (usually the
manufacturer or potential marketer), having screened the new molecule for pharmacological activity
and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in
humans. At that point, the molecule changes in legal status under the Federal Food, Drug, and
Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory
system.
An Investigator IND is submitted by a physician who both initiates and conducts an
investigation, and under whose immediate direction the investigational drug is administered or
dispensed. A physician might submit a research IND to propose studying an unapproved drug, or
an approved product for a new indication or in a new patient population.
Emergency Use IND allows the FDA to authorize use of an experimental drug in an
emergency situation that does not allow time for submission of an IND in accordance with 21CFR
, Sec. 312.23 or Sec. 312.20. It is also used for patients who do not meet the criteria of an existing
study protocol, or if an approved study protocol does not exist.
Treatment IND is submitted for experimental drugs showing promise in clinical testing for
serious or immediately life-threatening conditions while the final clinical work is conducted and
the FDA review takes place.
IND categories
Commercial
Research (non-commercial)
The IND application must contain information in three broad areas:
1. Animal Pharmacology and Toxicology Studies
Preclinical data to permit an assessment as to whether the product is reasonably safe for
initial testing in humans. Also included are any previous experience with the drug in humans
(often foreign use).
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2. Manufacturing Information
Information pertaining to the composition, manufacturer, stability, and controls used for
manufacturing the drug substance and the drug product. This information is assessed to ensure
that the company can adequately produce and supply consistent batches of the drug.
3. Clinical Protocols and Investigator Information
Detailed protocols for proposed clinical studies to assess whether the initial-phase trials
will expose subjects to unnecessary risks. Also, information on the
4. Qualifications of clinical investigators
professionals (generally physicians) who oversee the administration of the experimental
compound to assess whether they are qualified to fulfill their clinical trial duties. Finally,
commitments to obtain informed consent from the research subjects, to obtain review of the study
by an institutional review board (IRB), and to adhere to the investigational new drug regulations.
Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any
clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure
that research subjects will not be subjected to unreasonable risk.
The labeling of an investigational new drug
Mustincludethefollowingstatement:”Caution: New Drug-Limited by Federal (or United
States) law to investigational use.”
Must not be false or misleading and should not imply that the drug is safe or effective for
the investigational purpose.
Control of an Investigational New Drug
An investigational new drug may be given to participants only under supervision by the
principal investigator or by a sub-investigator. (Usually, the person supervising the administration
of an investigational new drug is a physician.) The investigator cannot supply the investigational
new drug to any person who is not authorized to receive it.
Research that involves the use of controlled substances must comply with U.S. Drug
Enforcement Administration regulations (21 CFR 1300-end). When studying an investigational
new drug that is considered a controlled substance, the investigator must take adequate precautions
to prevent theft or diversion of the drug into illegal channels of distribution. Such precautions
include storing the investigational new drug “in a securely locked, substantially constructed cabinet
or other securely locked, substantially constructeden closure, access to which is limited.” Promotion
of and Charging for Investigational New Drugs.
Neither an investigat or nor asponsormay promote (that is, end rse or advertise) an
investigational new drug as safe or effective for the investigational purpose. In addition: An
investigational new drug cannot be distributed commercially or in a test market.
An investigation cannot be prolonged “after finding that the results of the investigation
appear to establish sufficient data to support a marketing application.” In other words, if there is
good evidence that the investigational new drug is safe and effective, the study should be stopped
and no other participants enrolled.
Charging for an investigational new drug in a clinical trial is not permitted without approval
from the FDA unless the drug is being provided for treatments.

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Phases of Clinical Trials of Investigational New Drugs
Clinical trials of an investigational new drug are generally conducted in four phases, Phase
1 to Phase 4. Phase 0, or “exploratory” trials, also exist as small clinical trials (sometimes only a
few participants) that involve dosing at a sub-therapeutic level. Phase 0 trials are not as prevalent
as Phases 1-4. Each phase is designed to find out different information. Although the phases of a
trial are usually conducted sequentially (one after another), they sometimes overlap.
Individuals may be eligible for studies in different phases, depending on their age, general
condition, the type and stage of their disease, and previous therapy, if any.
1. Phase 1 Trials
Phase 1 trials are the first studies of an investigational new drug in humans. They are usually
conducted in healthy volunteers. In some cases, Phase 1 trials may be conducted in individuals
who have the disease the drug is intended to treat. Phase I trials generally involve between 20 and
80participants.
Phase 1 trials are designed:
Make a preliminary determination of the drug’s safety in humans. Identify some of the side
effects associated with the drug’s use.
Begin to define a safe therapeutic (healing) dose range.
2. Phase 2 Trials
Phase 2 trials are usually conducted in individuals who have the disease the drug is intended
to treat or are at high risk for developing the disease. Phase 2 trials are larger than Phase 1 trials
but still relatively small, usually involving no more than several hundred participants.
Phase 2 trials are designed to:
Beg into evaluate the drug’s effectiveness in treating or preventing the disease or condition
of interest.
Determine the optimal dosing of the drug.
Determine the common short-term side effects and risks associated with the drug.
3. Phase 3 Trials
Phase 3 trials are conducted after preliminary evidence from Phase 1 and 2 trials suggests
that the investigational new drug is safe and effective. They usually include between several
hundred and several thousand participants.
Phase 3 trials are designed to:
Gather additional information about the drug’s safety and effectiveness to evaluate whether
its benefits outweigh its risks.
Compare it to other commonly used treatments for the same condition (if available) or
compared to a placebo. These studies can be performed in a blinded manner.
Evaluate interactions with other treatments that may be used at the same time as the
investigational new drug.
Provide adequate information to determine the indication for which the drug will be labeled
fit is approved for marketing as well as any limitations on the drug’s use that should be stated in
the labeling. For example, if there were insufficient information to show that a drug can safely be
given to children, the labeling would restrict the drug’s use to adults.
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4. Phase 4 Trials
Phase 4 trials are conducted after the drug or treatment has been approved for marketing.
They are designed to:
Continue testing the drug or treatment to collect additional short-term safety information.
Collect information about the effect of the drug or treatment in various populations. Collect
information about side effects associated with long-term use of the drug
IND Protocol Amendments
The sponsor of an IND must submit a protocol amendment to the FDA: To describe any
changeina Phase1 protocol that significantly affects the safety of participants; or to describe any
change in a Phase 2 or Phase 3 protocol that significantly affects the safety of participants, the
scope of the investigation, or the scientific quality of the study.
IND Safety Reports
Sponsors must promptly review and investigate all information they receive relevant to the
safety of an investigational new drug that is received from any source, foreign or domestic, including
information derived from: Clinical or epidemiological studies, Animal studies, Commercial
marketing experience, Reports in the scientific literature, unpublished scientific papers, and Reports
from foreign regulatory authorities. The sponsor must notify the FDA of any unexpected fatal or
life-threatening experience associated with the use of the drug as soon as possible but not later
than 7 calendar days after the sponsor’s initial receipt of the information. Sponsors must provide
written notification to the FDA and to all investigators participating in a trial within 15 calendar
days of any adverse event that is:
Both serious, unexpected and reasonably likely to have been caused by the investigational
new drug. Subsequent, appropriate follow-up information must also be submitted, a sit becomes
available. The sponsor must also provide written notification of any finding from tests in laboratory
animals that suggests a significant risk for human participants. The written notification must be
provided as soon as possible and no later than15 calendar days after the sponsor receives the
information.
IND Information Amendments and Annual Reports
A sponsor must file an information amendment to report essential information about the
IND that is not within the scope of a protocol amendment, IND safety report, or annual report.
The following are examples of information that requires the filing of an information amendment:
New information about technical features of the drug, such a sitstoxicology or chemistry.
Discontinuation of a clinical investigation.
Within 60 days of the first anniversary of the date the IND went into effect, and every
subsequent year, a sponsor must submit a brief report of the progress of the investigation. This
annual report must include: A brief summary of the status of each study in progress or completed.
A summary of the most frequent and most serious adverse experiences. A summary of al lIND
safety reports submitted. A list of participants who died during participation in the investigation,
with the cause of death for each participant. A list of participants who dropped out as a result of
any adverse experience, whether or not the adverse experience is thought to be related to the
investigational new drug. A summary of the general investigational plan for the upcoming year.
An updated Investigator’s Brochure, if available. A summary of any foreign market developments.
A summary of any outstanding business with the FDA regarding the IND (i.e. a response to an
FDA request for information)
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 Investigational New Drugs Responsibilities
1. Responsibilities of Sponsors
Both sponsor sand investing at ors who are involved in conducting a clinical trial under an
IND filed with the FDA must accept and fulfill certain responsibilities.
Sponsors’ responsibilities include: Selecting qualified investigators, providing investigators
with the information they need to conduct the investigation, ensuring proper monitoring of the
trial, Ensuring the trial is conducted according to the plan and protocols contained in the IND,
Informing the FDA and all investigators of significant new adverse effects or risks that are
reasonably likely to be caused by the investigational new drug. Maintaining proper records,
disposing of unused supplies of the investigational new drug. Unless the sponsor is a sponsor-
investigator, the sponsor does not actually conduct the investigation. Based on GCP guidelines,
other Sponsor responsibilities include (ICH GCP E6, 5.12; 5.13; 5.14): Ensuring that the
Investigational Product is manufactured in accordance with Good Manufacturing Practices.
Ensuring that Investigational Product is packaged in a way that prevents contamination and
unacceptable deterioration during transport and storage. Supplying investigators/institutions with
the Investigational Product. Having written procedures that include instructions on the handling
and storage of Investigational product that sites should follow. Maintaining sufficient quantities
of the Investigational Product used in the trial to reconfirm specifications should he need arise.
The above represent good examples of responsibilities the Sponsor may transfer to a Contract
Research Organization (CRO), such as a clinical coordinating center. However, the ultimate
responsibility for Investigational Product resides with the Sponsor. Any Investigational Product-
related duties and functions that are transferred to and assumed by a CRO are specified in writing.
2. Responsibilities of Investigators
Investigators’ responsibilities include:
Providing the sponsor with a completed, signed Statement of Investigator. (Form FDA 1572.
Conducting the trial in accordance with the signed investigator statement, protocol, and applicable
regulations. Protecting the rights, safety, and welfare of trial participants. Obtaining informed
consent from all trial participants. Maintaining proper records. Furnishing all required progress
reports, safety reports, financial disclosure reports, and a final report. Complying with Institutional
Review Board review and Ensuring the proper handling of controlled substances. This topic is
also discussed in the Roles and Responsibilities module. Based on GCP guidelines, other
Investigator responsibilities include (ICH GCP E6, 4.6): Ensuring Investigational Product
Accountability Assigning duties for Investigational Products to a pharmacist or an appropriate
individual who has the necessary license for dispensing. Maintaining records of the Investigational
Product from delivery at the site to dispensing to the participant as well as use by the participant,
return by the participant, and reconciling all product prior to destruction. Ensuring that the
Investigational Product is used in accordance with the approved protocol. Explaining the correct
use of the Investigational Product to each participant and checking at intervals that each participant
is following instructions properly.

New Drug Application (NDA)

Background
For decades, the regulation and control of new drugs in the United States has been based on
28
the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved
NDA before U.S. commercialization. The NDA application is the vehicle through which drug
sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in
the United State. The data gathered during the animal studies and human clinical trials of
an Investigational New Drug (IND) become part of the NDA.
The goals of the NDA are to provide enough information to permit FDA reviewer to reach
the following key decisions:
 Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the
drug outweigh the risks.
 Whether the drug’s proposed labeling (package insert) is appropriate, and what it should
contain.
 Whether the methods used in manufacturing the drug and the controls used to maintain the
drug’s quality are adequate to preserve the drug’s identity, strength, quality and purity.
NDA is an application submitted to the FDA for permission to market a new drug. To obtain
this permission a sponsor submits preclinical and clinical test data to NDA for analyzing the drug
information, description of manufacturing procedures.
After NDA received by the agency, it undergoes a technical screening. This evaluation ensures
that sufficient data and information have been submitted in each area to justify “filing” the
application that is FDA formal review. At the conclusion of FDA review of an NDA, there are 3
possible actions that can send to sponsor: Not approvable- in this letter list of deficiencies and
explain the reason. Approvable - it means that the drug can be approved but minor deficiencies
that can be corrected like-labeling changes and possible request commitment to do post-approval
studies. Approval- it states that the drug isapproved. If the action taken is either an approvable or
a not approvable, then FDA provides applicant with an opportunity to meet with agency and
discuss the deficiencies.
New Drug Application
A new drug application (NDA) is a comprehensive document that must be submitted to the
U.S. Food and Drug Administration (FDA) in order to request approval for marketing a new drug
in the United States.
NDA Classifications
NDA Classifications CDER classifies new drug applications with a code that reflects both
the type of drug being submitted and its intended uses.
- New Molecular Entity
- New Salt of Previously Approved Drug
- New Formulation of Previously Approved Drug
- New Combination of Two or More Drugs
- Already Marketed Drug Product – Duplication by new manufacturer
- New Indication for Already Marketed Drug, including switch in status to OTC (conversion
of prescription drug to OTC)
- Already Marketed Drug Product without previously Approved NDA
NDA Requirements
- Content and format of application
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- Formatting, assembling and submitting new drug and antibiotic applications
- NDA summary format and content
- NDA technical sections
- Abbreviated new drug application
1. Content and format of application
Although the exact requirements are a function of the nature of a specific drug, the NDA
must provide all relevant data and information that a sponsor has collected during the product’s
research and development.
2. Formatting, assembling and submitting new drug and antibiotic
applications
A. Application format
The NDA regulations require the submission of Archival copy and Review copy.
i. Archival copy :
This is a complete copy of an application submission and is intended to serve as a
reference source for FDA reviewers. This contains information which not contained in
the review copy.
ii. Review copy :
It is divided into five (or six) sections containing technical and scientific information
required by FDA reviewers. Each of sections of review copy is separately bound. It
should be provided with following: A copy of cover letter. A copy of application form
(FDA 356h) A copy of overall summary A copy of index to the entire application An
index to the specific review section Both copies are submitted in hard copy.
B. Assembling the application
Folders
Because of the procedure used at the FDA to file and retrieve material from the document
rooms where applications are kept, it is necessary that applicants use the colored folders to bind
the archival copy and each technical section. The cover of each folder should bear the NDA
number (if known), name of applicant and name of drug product.
Paper size and binding
All applications must be bound on the left side of the page using the Unite States standard
size loose leaf page. (8.5” x11” ).
Pagination
All pages in the application must be numbered and numbering of review copy pages should
be same as the numbering of corresponding pages in archival copy.
Volume size and identification
Volume submitted in hard copy form should be no more than 2 inches thick.
Packing carton
The box size of 14” *12” *9.5” is recommended for shipment of applications to FDA.
Because ANDAs are handled and stored separately, smaller boxes may be appropriate for them.
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Supplements, Amendments and Post marketing Reports
The submission format for amendments to pending applications and supplements to approved
applications will be same as an original application. Each submission will consist of two copies:
a complete archival copy and an appropriately segmented review copy. Amendments, supplements,
resubmissions annual reports and other correspondence concerning full applications should be
addressed to appropriate FDA reviewing divisions.
C. Application content
Full application
Archival copy
The archival copy should confirm the agreement between the FDA and the applicant. The
letter should cite any relevant meetings by date and topic, and identify one or more persons the
FDA may contact regarding the application. The letter may include any other information the
applicant wishes to convey to the FDA about the application. The archival copy is required to
contain the following: Application form (FDA 356h) it serves as a cover sheet for the application,
contains basic identifying information about the applicant and the drug product. The application
form, as well as the index and the summary should be bound together in a single volume. Patent
information on the applicant’s drug and a patent certification with respect to the drug should be
submitted on a separate piece of paper attached to the application form itself.
3. NDA Summary Format and Content
Summary should provide sufficient detail. Data should be provided in tabular or graphical
form,. Summary should be between 50-200 pages.
Annotated package insert
This section include proposed text of the labeling for the product. The proposed text of the
package labeling must be annotated by reference to volume and page number to the information
in the summary and in technical sections of the applications.
Pharmacological class, scientific rationale, intended use and potential
clinical benefits
A brief statement should be included to identify the pharmacological class of the drug, the
scientific rationale for the drug, its intended use, and its potential clinical benefits.
Chemistry, Manufacturing and Controls
This summary must provide overview of the drug substances and the drug product.
1. Drug substance: It includes description about of drug substance, physical and chemical
characteristics and stability of the drug substance.
2. Drug product: It includes information about:
a. Composition and dosage form
b. Name and address of manufacturer
c. Container and closure system
d. Stability
e. Specifications for drug product and test methods to assure the specifications

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Foreign Marketing History
If the product is marketed outside the U.S., regardless of the dosage form, strength, salt,
ester, or complex of the drug, the marketing history should be provided. This should include a list
of countries in which drug product is marketed, with dates of marketing, if known. It must also
include a list of any countries in which the drug has been withdrawn for any reason relating to
safety or efficacy. Specific reason for withdrawal should be given.
Non- clinical Pharmacology and Toxicology Summary:
It includes information about:
3. Pharmacology studies
4. Acute toxicity studies
5. Multi dose toxicity studies
6. Carcinogenicity studies
7. Special toxicity studies
8. Reproduction studies
9. Mutagenicity studies
10. ADME studies
Human Pharmacokinetics and bio-availability Summary
It includes brief description about bio-availability study of drug, pharmacokinetic
characteristic of active ingredient and dissolution profile of drug.
Microbiology Summary
It provides summary of results of the microbiologic studies conducted with anti-infective
and antiviral drug. This includes mechanism of action, antimicrobial spectrum of action and
mechanism of resistance to the drug.
Clinical Data Summary and Results of Statistical Analysis
It is the basis of efficacy and safety that will determine an NDA approval. The Clinical Data
Summary and Results of Statistical Analysis are divided into several parts as described below:
Clinical pharmacology Overview of Clinical Studies Controlled Clinical Studies Uncontrolled
Clinical Studies Other studies and Information Safety summary (general Safety Conclusions).
4. NDA technical sections
This includes brief description of the following sections.
Chemistry, Manufacturing and Controls
It is the most critical portion of NDA or ANDA. This section must fully describe the
composition of the drug substance (active ingredient), and its synthesis (or isolation) and
purification, as well as applicable process controls, specifications, and analytical test methods.
Nonclinical Pharmacology and Toxicology
It provides a description or summary of all animal and invitro studies with the drug.
1. Pharmacology Studies.
2. Acute Toxicity Studies.
3. Sub chronic/Chronic/Carcinogenicity Studies.
32
4. Special Toxicity Studies.
5. Reproduction Studies.
6. Mutagenicity Studies.
7. ADME Studies.
Human Pharmacokinetics and bio-availability Section
For a new chemical entity (NCE), it is desirable to determine its bio-availability and
pharmacokinetics from the dosage form, except that for certain dosage forms (e.g., iv solutions)
100% bio-availability may be assumed. For solid oral dosage forms (e.g., capsule or tablet) a
bioequivalence study is often necessary to demonstrate that formulation proposed for marketing
is bioequivalent to whatever formulations may have been employed in early clinical trial. The
summary should include a table with following pharmacokinetic parameter: Cmax, AUC, Tmax,
kel, Vd, plasma and renal clearance and urine excretion.
Microbiology
This section is of major importance for anti-infective drugs and includes data on the
biochemical basis of the drug’s action and its antimicrobial spectra; any known mechanisms of
resistance to the drug; and clinical laboratory methods.
Clinical Data Section
It is the most important and most complicated section of an NDA. It is the part that provides
the safety and efficacy data on the drug for its intended use.
Outline of Clinical Section
It includes
1. List of investigators; List of INDs and NDAs
2. Background / Overview of clinical investigations
3. Clinical pharmacology
4. Controlled clinical studies
5. Uncontrolled clinical studies
6. Other studies and information
7. Integrated summary of efficacy
8. Integrated summary of safety
9. Drug abuse and over dosage information
10. Integrated summary of benefits and risk of drugs
Samples, Methods Validation and Labeling
Samples should not be submitted to the FDA with the application. The reviewing chemist
will contact the applicant and provide the laboratory address where samples should be sent. The
applicant should prepare four representative samples in sufficient quantity to permit FDA to perform
each test described in the application three times to determine whether the drug substance and
drug product meet the specification given in the application. The archival copy of an application
is required to contain copies of the label and all labeling proposed for the drug product. Methods
validation data must be provided in triplicate because copies are forwarded to two FDA laboratories.

33
Case Report Forms and Tabulations
The sponsor must submit data tabulations from each Phase II and Phase III study and also
the case study report form for every clinical trial patient who died or withdrew from the study
because of an adverse event.
Patent Information
Information must be submitted regarding any patent held by the sponsor that covers the
drug substance, formulation, and composition of the drug product, or method of use. Upon approval
of the NDA, this information is published in the FDA’s Orange Book (known formally as Approved
Drug Products with Therapeutic Equivalence Evaluations) and serves as a guide to firms wishing
to develop generic copies of the innovator’s product.
5. Abbreviated new drug application
An abbreviated new drug application (ANDA) contains data which is submitted to FDA for
the review and potential approval of a generic drug product. Once approved, an applicant may
manufacture and market the generic drug product to provide a safe, effective, lower cost alternative
to the brand-name drug it references.
Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted in the form and
contain the information, as appropriate for the particular submission, required under this section.
Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA
for a new chemical entity will generally contain an application form, an index, a summary, five
or six technical sections, case report tabulations of patient data, case report forms, drug samples,
and labeling, including, if applicable, any Medication Guide required under part 208 of this chapter.
Other NDAs will generally contain only some of those items, and information will be limited to
that needed to support the particular submission. These include an NDA of the type described in
section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, an amendment, and a supplement.
The NDA is required to contain reports of all investigations of the drug product sponsored by
the applicant, and all other information about the drug pertinent to an evaluation of the NDA that
is received or otherwise obtained by the applicant from any source. FDA will maintain guidance
documents on the format and content of NDAs to assist applicants in their preparation.
(a) Application form. The applicant must submit a completed and signed application form that
contains the following:
(1) The name and address of the applicant; the date of the NDA; the NDA number if
previously issued (for example, if the NDA is a resubmission or an amendment or
supplement); the name of the drug product, including its established, proprietary, code,
and chemical names; the dosage form and strength; the route of administration; the
identification numbers of all INDs (as defined in § 312.3(b) of this chapter) that are
referenced in the NDA; the identification numbers of all drug master files and
other applications under this part that are referenced in the NDA; and the drug product’s
proposed indications for use.
(2) A statement whether the submission is an original submission, a 505(b)(2) application,
a resubmission, or a supplement to an application under § 314.70.
(3) A statement whether the applicant proposes to market the drug product as a prescription
or an over-the-counter product.
(4) A check-list identifying what enclosures required under this section the applicant is
submitting.
34
 (5) The applicant, or the applicant’s attorney, agent, or other authorized official must sign
the NDA. If the person signing the NDA does not reside or have a place of business
within the United States, the NDA is required to contain the name and address of, and
be countersigned by, an attorney, agent, or other authorized official who resides
or maintains a place of business within the United States.
(b) Index. The archival copy of the NDA is required to contain a comprehensive index by volume
number and page number to the summary under paragraph (c) of this section, the technical sections
under paragraph (d) of this section, and the supporting information under paragraph (f) of this
section.
(c) Summary.
(1) An NDA is required to contain a summary of the NDA in enough detail that the reader
may gain a good general understanding of the data and information in the NDA,
including an understanding of the quantitative aspects of the data. The summary is not
required for supplements under § 314.70. Resubmissions of an NDA should contain
an updated summary, as appropriate. The summary should discuss all aspects of the
NDA, and synthesize the information into a well-structured and unified document.
The summary should be written at approximately the level of detail required for
publication in, and meet the editorial standards generally applied by, refereed scientific
and medical journals. In addition to the agency personnel reviewing the summary in
the context of their review of the NDA, FDA may furnish the summary to FDA advisory
committee members and agency officials whose duties require an understanding of
the NDA. To the extent possible, data in the summary should be presented in tabular
and graphic forms. FDA has prepared a guideline under § 10.90(b) that provides
information about how to prepare a summary. The summary required under this
paragraph may be used by FDA or the applicant to prepare the Summary Basis of
Approval document for public disclosure (under § 314.430(e)(2)(ii)) when the NDA
is approved.
(2) The summary is required to contain the following information:
(i) The proposed text of the labeling, including, if applicable, any Medication Guide
required under part 208 of this chapter, for the drug, with annotations to the information
in the summary and technical sections of the NDA that support the inclusion of each
statement in the labeling, and, if the NDA is for a prescription drug, statements
describing the reasons for omitting a section or subsection of the labeling format in §
201.57 of this chapter.
(ii) A statement identifying the pharmacologic class of the drug and a discussion of
the scientific rationale for the drug, its intended use, and the potential clinical benefits
of the drug product.
(iii) A brief description of the marketing history, if any, of the drug outside the United
States, including a list of the countries in which the drug has been marketed, a list of
any countries in which the drug has been withdrawn from marketing for any reason
related to safety or effectiveness, and a list of countries in which applications for
marketing are pending. The description is required to describe both marketing by
the applicant and, if known, the marketing history of other persons.
(iv) A summary of the chemistry, manufacturing, and controls section of the NDA.
(v) A summary of the nonclinical pharmacology and toxicology section of the NDA.
35
 (vi) A summary of the human pharmacokinetics and bioavailability section of the NDA.
(vii) A summary of the microbiology section of the NDA (for anti-infective drugs
only).
(viii) A summary of the clinical data section of the NDA, including the results of
statistical analyses of the clinical trials.
(ix) A concluding discussion that presents the benefit and risk considerations related
to the drug, including a discussion of any proposed additional studies or surveillance
the applicant intends to conduct postmarketing.
(d) Technical sections. The NDA is required to contain the technical sections described below.
Each technical section is required to contain data and information in sufficient detail to permit the
agency to make a knowledgeable judgment about whether to approve the NDA or whether grounds
exist under section 505(d) of the Federal Food, Drug, and Cosmetic Act to refuse to approve the
NDA. The required technical sections are as follows:
(1) Chemistry, manufacturing, and controls section. A section describing the composition,
manufacture, and specification of the drug substance and the drug product, including the
following:
(i) Drug substance. A full description of the drug substance including its physical and
chemical characteristics and stability; the name and address of its manufacturer; the
method of synthesis (or isolation) and purification of the drug substance; the process
controls used during manufacture and packaging; and the specifications necessary to
ensure the identity, strength, quality, and purity of the drug substance and
the bioavailability of the drug products made from the substance, including, for
example, tests, analytical procedures, and acceptance criteria relating to stability,
sterility, particle size, and crystalline form. The NDA may provide additionally for the
use of alternatives to meet any of these requirements, including alternative sources,
process controls, and analytical procedures. Reference to the current edition of the
U.S. Pharmacopeia and the National Formulary may satisfy relevant requirements in
this paragraph.
(ii) (a) Drug product. A list of all components used in the manufacture of the drug
product (regardless of whether they appear in the drug product) and a statement of the
composition of the drug product; the specifications for each component; the name and
address of each manufacturer of the drug product; a description of the manufacturing
and packaging procedures and in-process controls for the drug product;
the specifications necessary to ensure the identity, strength, quality, purity, potency,
and bioavailability of the drug product, including, for example, tests, analytical
procedures, and acceptance criteria relating to sterility, dissolution rate, container
closure systems; and stability data with proposed expiration dating. The NDA may
provide additionally for the use of alternatives to meet any of these requirements,
including alternative components, manufacturing and packaging procedures, in-process
controls, and analytical procedures. Reference to the current edition of the U.S.
Pharmacopeia and the National Formulary may satisfy relevant requirements in this
paragraph.
(b) Unless provided by paragraph (d)(1)(ii)(a) of this section, for each batch of the drug
product used to conduct a bioavailability or bioequivalence study described in §
320.38 or § 320.63 of this chapter or used to conduct a primary stability study: The

36
 batch production record; the specification for each component and for the drug product;
the names and addresses of the sources of the active and non-compendial
inactive components and of the container and closure system for the drug product; the
name and address of each contract facility involved in the manufacture, processing,
packaging, or testing of the drug product and identification of the operation performed
by each contract facility; and the results of any test performed on the components used
in the manufacture of the drug product as required by § 211.84(d) of this chapter and
on the drug product as required by § 211.165 of this chapter.
(c) The proposed or actual master production record, including a description of the
equipment, to be used for the manufacture of a commercial lot of the drug product or
a comparably detailed description of the production process for a representative batch
of the drug product.
(iii) Environmental impact. The NDA is required to contain either a claim for categorical
exclusion under § 25.30 or 25.31 of this chapter or an environmental assessment
under § 25.40 of this chapter.
(iv) The applicant may, at its option, submit a complete chemistry, manufacturing, and
controls section 90 to 120 days before the anticipated submission of the remainder of
the NDA. FDA will review such early submissions as resources permit.
(v) The applicant must include a statement certifying that the field copy of the NDA has
been provided to the applicant’s home FDA district office.
(2) Nonclinical pharmacology and toxicology section. A section describing, with the aid of
graphs and tables, animal and in vitro studies with drug, including the following:
(i) Studies of the pharmacological actions of the drug in relation to its proposed therapeutic
indication and studies that otherwise define the pharmacologic properties of the drug or are
pertinent to possible adverse effects.
(ii) Studies of the toxicological effects of the drug as they relate to the drug’s intended
clinical uses, including, as appropriate, studies assessing the drug’s acute, subacute, and
chronic toxicity; carcinogenicity; and studies of toxicities related to the drug’s particular
mode of administration or conditions of use.
(iii) Studies, as appropriate, of the effects of the drug on reproduction and on the developing
fetus.
(iv) Any studies of the absorption, distribution, metabolism, and excretion of the drug in
animals.
(v) For each nonclinical laboratory study subject to the good laboratory practice regulations
under part 58 a statement that it was conducted in compliance with the good laboratory
practice regulations in part 58, or, if the study was not conducted in compliance with those
regulations, a brief statement of the reason for the noncompliance.
(3) Human pharmacokinetics and bio-availability section. A section describing the human
pharmacokinetic data and human bioavailability data, or information supporting a waiver
of the submission of in vivo bioavailability data under subpart B of part 320, including the
following:
(i) A description of each of the bioavailability and pharmacokinetic studies of the drug in
humans performed by or on behalf of the applicant that includes a description of the analytical
procedures and statistical methods used in each study and a statement with respect to each
37
 study that it either was conducted in compliance with the institutional review board
regulations in part 56, or was not subject to the regulations under § 56.104 or § 56.105, and
that it was conducted in compliance with the informed consent regulations in part 50.
(ii) If the NDA describes in the chemistry, manufacturing, and controls section tests,
analytical procedures and acceptance criteria needed to assure the bioavailability of the drug
product or drug substance, or both, a statement in this section of the rationale for establishing
the tests, analytical procedures, and acceptance criteria, including data and information
supporting the rationale.
(iii) A summarizing discussion and analysis of the pharmacokinetics and metabolism of
the active ingredients and the bioavailability or bioequivalence, or both, of the drug product.
(4) Microbiology section. If the drug is an anti-infective drug, a section describing the
microbiology data, including the following:
(i) A description of the biochemical basis of the drug’s action on microbial physiology.
(ii) A description of the antimicrobial spectra of the drug, including results of in vitro
preclinical studies to demonstrate concentrations of the drug required for effective use.
(iii) A description of any known mechanisms of resistance to the drug, including results of
any known epidemiologic studies to demonstrate prevalence of resistance factors.
(iv) A description of clinical microbiology laboratory procedures (for example, in vitro
sensitivity discs) needed for effective use of the drug.
(5) Clinical data section. A section describing the clinical investigations of the drug, including
the following:
(i) A description and analysis of each clinical pharmacology study of the drug, including
a brief comparison of the results of the human studies with the animal pharmacology and
toxicology data.
(ii) A description and analysis of each controlled clinical study pertinent to a proposed
use of the drug, including the protocol and a description of the statistical analyses used to
evaluate the study. If the study report is an interim analysis, this is to be noted and a projected
completion date provided. Controlled clinical studies that have not been analyzed in detail
for any reason (e.g., because they have been discontinued or are incomplete) are to be included
in this section, including a copy of the protocol and a brief description of the results and
status of the study.
(iii) A description of each uncontrolled clinical study, a summary of the results, and a brief
statement explaining why the study is classified as uncontrolled.
(iv) A description and analysis of any other data or information relevant to an evaluation
of the safety and effectiveness of the drug product obtained or otherwise received by
the applicant from any source, foreign or domestic, including information derived from
clinical investigations, including controlled and uncontrolled studies of uses of the drug
other than those proposed in the NDA, commercial marketing experience, reports in the
scientific literature, and unpublished scientific papers.
(v) An integrated summary of the data demonstrating substantial evidence of effectiveness
for the claimed indications. Evidence is also required to support the dosage and administration
section of the labeling, including support for the dosage and dose interval recommended.
The effectiveness data must be presented by gender, age, and racial subgroups and must
identify any modifications of dose or dose interval needed for specific subgroups.
38
Effectiveness data from other subgroups of the population of patients treated, when
appropriate, such as patients with renal failure or patients with different levels of severity of
the disease, also must be presented.
(vi) A summary and updates of safety information, as follows:
(a)The applicant must submit an integrated summary of all available information about
the safety of the drug product, including pertinent animal data, demonstrated or potential
adverse effects of the drug, clinically significant drug/drug interactions, and other
safety considerations, such as data from epidemiological studies of related drugs. The
safety data must be presented by gender, age, and racial subgroups. When appropriate,
safety data from other subgroups of the population of patients treated also must be
presented, such as for patients with renal failure or patients with different levels of
severity of the disease. A description of any statistical analyses performed in analyzing
safety data should also be included, unless already included under paragraph (d)(5)(ii) of
this section.
(b)The applicant must, under section 505(i) of the Federal Food, Drug, and Cosmetic
Act, update periodically its pending NDA with new safety information learned about
the drug that may reasonably affect the statement of contraindications, warnings,
precautions, and adverse reactions in the draft labeling and, if applicable, any
Medication Guide required under part 208 of this chapter. These “safety update reports”
must include the same kinds of information (from clinical studies, animal studies, and
other sources) and must be submitted in the same format as the integrated summary in
paragraph (d)(5)(vi)(a) of this section. In addition, the reports must include the case
report forms for each patient who died during a clinical study or who did not complete
the study because of an adverse event (unless this requirement is waived).
The applicant must submit these reports (1) 4 months after the initial submission; (2)
in a resubmission following receipt of a complete response letter; and (3) at other times
as requested by FDA. Before submitting the first such report, applicants are encouraged
to consult with FDA regarding further details on its form and content.
(vii) If the drug has a potential for abuse, a description and analysis of studies or information
related to abuse of the drug, including a proposal for scheduling under the Controlled
Substances Act. A description of any studies related to overdosage is also required, including
information on dialysis, antidotes, or other treatments, if known.
(viii) An integrated summary of the benefits and risks of the drug, including a discussion of
why the benefits exceed the risks under the conditions stated in the labeling.
(ix) A statement with respect to each clinical study involving human subjects that it either
was conducted in compliance with the institutional review board regulations in part 56, or
was not subject to the regulations under § 56.104 or § 56.105, and that it was conducted
in compliance with the informed consent regulations in part 50.
(x) If a sponsor has transferred any obligations for the conduct of any clinical study to a
contract research organization, a statement containing the name and address of the contract
research organization, identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have been transferred, a
general statement of this transfer - in lieu of a listing of the specific obligations transferred
- may be submitted.
(xi) If original subject records were audited or reviewed by the sponsor in the course of

39
 monitoring any clinical study to verify the accuracy of the case reports submitted to the
sponsor, a list identifying each clinical study so audited or reviewed.
(6) Statistical section. A section describing the statistical evaluation of clinical data, including
the following:
(i) A copy of the information submitted under paragraph (d)(5)(ii) of this section
concerning the description and analysis of each controlled clinical study, and the
documentation and supporting statistical analyses used in evaluating the controlled clinical
studies.
(ii) A copy of the information submitted under paragraph (d)(5)(vi)(a) of this section
concerning a summary of information about the safety of the drug product, and the
documentation and supporting statistical analyses used in evaluating the safety information.
(7) Pediatric use section. A section describing the investigation of the drug for use in pediatric
populations, including an integrated summary of the information (the clinical pharmacology
studies, controlled clinical studies, or uncontrolled clinical studies, or other data or
information) that is relevant to the safety and effectiveness and benefits and risks of the
drug in pediatric populations for the claimed indications, a reference to the full descriptions
of such studies provided under paragraphs (d)(3) and (d)(5) of this section, and information
required to be submitted under § 314.55.
(e) Samples and labeling
(1) Upon request from FDA, the applicant must submit the samples described below to the
places identified in the Agency’s request. FDA generally will ask applicants to submit samples
directly to two or more Agency laboratories that will perform all necessary tests on the
samples and validate the applicant’s analytical procedures.
(i) Four representative samples of the following, each sample in sufficient quantity to
permit FDA to perform three times each test described in the NDA to determine whether
the drug substance and the drug product meet the specifications given in the NDA:
(a) The drug product proposed for marketing;
(b) The drug substance used in the drug product from which the samples of the drug
product were taken; and
(c) Reference standards and blanks (except that reference standards recognized in an
official compendium need not be submitted).
(ii) Samples of the finished market package, if requested by FDA.
(2) The applicant must submit the following in the archival copy of the NDA:
(i) Three copies of the analytical procedures and related descriptive information contained
in the chemistry, manufacturing, and controls section under paragraph (d)(1) of this section
for the drug substance and the drug product that are necessary for FDA’s laboratories to
perform all necessary tests on the samples and to validate the applicant’s analytical
procedures. The related descriptive information includes a description of each sample; the
proposed regulatory specifications for the drug; a detailed description of the methods of
analysis; supporting data for accuracy, specificity, precision and ruggedness; and complete
results of the applicant’s tests on each sample.
(ii) Copies of the label and all labeling for the drug product (including, if applicable, any
Medication Guide required under part 208 of this chapter) for the drug product (4 copies of

40
 draft labeling or 12 copies of final printed labeling).
(f) Case report forms and tabulations. The archival copy of the NDA is required to contain
the following case report tabulations and case report forms:
(1) Case report tabulations. The NDA is required to contain tabulations of the data from each
adequate and well-controlled study under § 314.126 (Phase 2 and Phase 3 studies as described
in §§ 312.21 (b) and (c) of this chapter), tabulations of the data from the earliest clinical
pharmacology studies (Phase 1 studies as described in § 312.21(a) of this chapter), and
tabulations of the safety data from other clinical studies. Routine submission of other patient
data from uncontrolled studies is not required. The tabulations are required to include the
data on each patient in each study, except that the applicant may delete those tabulations
which the agency agrees, in advance, are not pertinent to a review of the drug’s safety or
effectiveness. Upon request, FDA will discuss with the applicant in a “pre-NDA” conference
those tabulations that may be appropriate for such deletion. Barring unforeseen circumstances,
tabulations agreed to be deleted at such a conference will not be requested during the conduct
of FDA’s review of the NDA. If such unforeseen circumstances do occur, any request for
deleted tabulations will be made by the director of the FDA division responsible for reviewing
the NDA, in accordance with paragraph (f)(3) of this section.
(2) Case report forms. The NDA is required to contain copies of individual case report forms
for each patient who died during a clinical study or who did not complete the study because
of an adverse event, whether believed to be drug related or not, including patients receiving
reference drugs or placebo. This requirement may be waived by FDA for specific studies if
the case report forms are unnecessary for a proper review of the study.
(3) Additional data. The applicant must submit to FDA additional case report forms and
tabulations needed to conduct a proper review of the NDA, as requested by the director of
the FDA division responsible for reviewing the NDA. The applicant’s failure to submit
information requested by FDA within 30 days after receipt of the request may result in the
agency viewing any eventual submission as a major amendment under § 314.60 and extending
the review period as necessary. If desired by the applicant, the FDA division director will
verify in writing any request for additional data that was made orally.
(4) Presentation and format. Applicants are invited to meet with FDA before submitting an
NDA to discuss the presentation and format of supporting information. If the applicant and
FDA agree, the applicant may submit tabulations of patient data and case report forms in an
alternate form.
(g) Other. The following general requirements apply to the submission of information within
the summary under paragraph (c) of this section and within the technical sections
under paragraph (d) of this section.
(1) The applicant ordinarily is not required to resubmit information previously submitted, but
may incorporate the information by reference. A reference to information submitted previously
is required to identify the file by name, reference number, volume, and page number in the
agency’s records where the information can be found. A reference to information submitted
to the agency by a person other than the applicant is required to contain a written statement
that authorizes the reference and that is signed by the person who submitted the information.
(2) The applicant must submit an accurate and complete English translation of each part of the
NDA that is not in English. The applicant must submit a copy of each original literature
publication for which an English translation is submitted.

41
(3) If an applicant who submits an NDA under section 505(b) of the Federal Food, Drug, and
Cosmetic Act obtains a “right of reference or use,” as defined under § 314.3(b), to an
investigation described in clause (A) of section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act, the applicant must include in its NDA a written statement signed by the owner
of the data from each such investigation that the applicant may rely on in support of the
approval of its NDA, and provide FDA access to, the underlying raw data that provide the
basis for the report of the investigation submitted in its NDA.
(h) Patent information. The NDA is required to contain the patent information described under §
314.53.
(i) Patent certification -
(I) Contents. A 505(b)(2) application is required to contain the following:
(i) Patents claiming drug substance, drug product, or method of use.
(A) An appropriate patent certification or statement with respect to each patent issued
by the U.S. Patent and Trademark Office that, in the opinion of the applicant and to
the best of its knowledge, claims the drug substance or drug product on which
investigations that are relied upon by the applicant for approval of its
505(b)(2) application were conducted or that claims an approved use for such drug
and for which information is required to be filed under section 505(b) and (c) of
the Federal Food, Drug, and Cosmetic Act and § 314.53. For each such patent,
the applicant must provide the patent number and certify, in its opinion and to the
best of its knowledge, one of the following circumstances:
(1) That the patent information has not been submitted to FDA. The applicant must
entitle such a certification “Paragraph I Certification”;
(2) That the patent has expired. The applicant must entitle such a certification
“Paragraph II Certification”;
(3) The date on which the patent will expire. The applicant must entitle such a
certification “Paragraph III Certification”; or
(4) (i) That the patent is invalid, unenforceable, or will not be infringed by the
manufacture, use, or sale of the drug product for which the
505(b)(2) application is submitted. The applicant must entitle such a certification
“Paragraph IV Certification”. This certification must be submitted in the
following form:
I, (name of applicant), certify that Patent No. ____ (is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of) (name of proposed drug product) for which this
505(b)(2) application is submitted.
(ii) The certification must be accompanied by a statement that the applicant will comply
with the requirements under § 314.52(a) with respect to providing a notice to each owner
of the patent or its representative and to the NDA holder (or, if the NDA holder does not
reside or maintain a place of business within the United States, its attorney, agent, or
other authorized official) for the drug product that is claimed by the patent or a use of
which is claimed by the patent and with the requirements under § 314.52(b) with respect
to sending the notice and under § 314.52(c) with respect to the content of the notice.
(B) If the drug on which investigations that are relied upon by the applicant were
conducted is itself a licensed generic drug of a patented drug first approved under
section 505(b) of the Federal Food, Drug, and Cosmetic Act, an appropriate patent
42
 certification or statement under this section with respect to each patent that claims
the first-approved patented drug or that claims an approved use for such a drug.
(C) If, before the date of submission of an original 505(b)(2) application, there is a drug
product approved in an NDA that is pharmaceutically equivalent to the drug
product for which the original 505(b)(2) application is submitted, an
appropriate patent certification or statement under this section with respect to each
patent that claims the drug substance or drug product or that claims an approved
use for one such drug product.
(iii) No relevant patents. If, in the opinion of the applicant and to the best of its knowledge,
there are no patents described in paragraph (i)(1)(i) of this section, a certification in the
following form:
In the opinion and to the best knowledge of (name of applicant), there are no patents
that claim the drug or drugs on which investigations that are relied upon in this
505(b)(2) application were conducted or that claim a use of such drug or drugs.
(iv) Method-of-use patent.
(A) If information that is submitted under section 505(b) or (c) of the Federal Food,
Drug, and Cosmetic Act and § 314.53 is for a method-of-use patent, and the labeling
for the drug product for which the applicant is seeking approval does not include
an indication or other condition of use that is covered by the method-of-use patent,
a statement explaining that the method-of-use patent does not claim a proposed
indication or other condition of use.
(B) If the labeling of the drug product for which the applicant is seeking approval
includes an indication or other condition of use that, according to the patent
information submitted under section 505(b) or (c) of the Federal Food, Drug, and
Cosmetic Act and § 314.53 or in the opinion of the applicant, is claimed by a method-
of-use patent, the applicant must submit an applicable certification under paragraph
(i)(1)(i) of this section.
(2) [Reserved]
(3) Licensing agreements. If a 505(b)(2) application is submitted for a drug or method of using
a drug claimed by a patent and the applicant has a licensing agreement with the patent owner,
the applicant must submit a paragraph IV certification as to that patent and a statement that
the applicant has been granted a patent license. If the patent owner consents to approval of
the 505(b)(2) application (if otherwise eligible for approval) as of a specific date, the
505(b)(2) application must contain a written statement from the patent owner that it has a
licensing agreement with the applicant and that it consents to approval of the
505(b)(2) application as of a specific date.
(4) Untimely filing of patent information.
(i) If a patent described in paragraph (i)(1)(i)(A) of this section is issued and the holder of
the approved NDA for the patented drug does not file with FDA the required information
on the patent within 30 days of issuance of the patent, an applicant who submitted a
505(b)(2) application that, before the submission of the patent information, contained
an appropriate patent certification or statement is not required to submit a patent
certification or statement to address the patent or patent information that is late-listed
with respect to the pending 505(b)(2) application. Except as provided in § 314.53(f)(1),

43
 an NDA holder’s amendment to the description of the approved method(s) of use claimed
by the patent will be considered untimely filing of patent information unless:
(A) The amendment to the description of the approved method(s) of use claimed by the
patent is submitted within 30 days of patent issuance;
(B) The amendment to the description of the approved method(s) of use claimed by the
patent is submitted within 30 days of approval of a corresponding change to product
labeling; or
(C) The amendment to the description of the approved method(s) of use claimed by the
patent is submitted within 30 days of a decision by the U.S. Patent and Trademark
Office or by a Federal district court, the Court of Appeals for the Federal Circuit, or
the U.S. Supreme Court that is specific to the patent and alters the construction of a
method-of-use claim(s) of the patent, and the amendment contains a copy of the
decision.
(ii) An applicant whose 505(b)(2) application is submitted after the NDA holder’s untimely
filing of patent information or whose 505(b)(2) application was previously filed but did
not contain an appropriate patent certification or statement at the time of the patent
submission must submit a certification under paragraph (i)(1)(i) of this section and/or a
statement under paragraph (i)(1)(iii) of this section as to that patent.
(5) Disputed patent information.
If an applicant disputes the accuracy or relevance of patent information submitted to FDA,
the applicant may seek a confirmation of the correctness of the patent information in accordance
with the procedures under § 314.53(f). Unless the patent information is withdrawn,
the applicant must submit an appropriate certification or statement for each listed patent.
(6) Amended certifications.
A patent certification or statement submitted under paragraphs (i)(1)(i) through (iii) of this
section may be amended at any time before the approval of the 505(b)(2) application.
An applicant must submit an amended certification as an amendment to a pending
505(b)(2) application. If an applicant with a pending 505(b)(2) application voluntarily makes
a patent certification for an untimely filed patent, the applicant may withdraw the patent
certification for the untimely filed patent. Once an amendment is submitted to change the
certification, the 505(b)(2) application will no longer be considered to contain the prior
certification.
(i) After finding of infringement. An applicant who has submitted a paragraph IV
certification and is sued for patent infringement must submit an amendment to change
its certification if a court enters a final decision from which no appeal has been or can
be taken, or signs and enters a settlement order or consent decree in the action that
includes a finding that the patent is infringed, unless the final decision, settlement order,
or consent decree also finds the patent to be invalid. In its amendment, the applicant must
certify under paragraph (i)(1)(i)(A)(3) of this section that the patent will expire on a
specific date or, with respect to a patent claiming a method of use, the applicant may
instead provide a statement under paragraph (i)(1)(iii) of this section if
the applicant amends its 505(b)(2) application such that the applicant is no longer
seeking approval for a method of use claimed by the patent. Once an amendment for
the change has been submitted, the 505(b)(2) application will no longer be considered

44
 to contain a paragraph IV certification to the patent. If a final decision finds the patent
to be invalid and infringed, an amended certification is not required.
(ii) After request to remove a patent or patent information from the list. If the
list reflects that an NDA holder has requested that a patent or patent information be
removed from the list and no ANDA applicant is eligible for 180-day exclusivity based
on a paragraph IV certification to that patent, the patent or patent information will be
removed and any applicant with a pending 505(b)(2) application (including a tentatively
approved 505(b)(2) application) who has made a certification with respect to such patent
must submit an amendment to withdraw its certification. In the amendment,
the applicant must state the reason for withdrawing the certification or statement (that
the patent has been removed from the list). If the list reflects that an NDA holder has
requested that a patent or patent information be removed from the list and one or
more first applicants are eligible for 180-day exclusivity based on a paragraph IV
certification to that patent, the patent will remain listed until any 180-day exclusivity
based on that patent has expired or has been extinguished. A 505(b)(2) applicant is not
required to provide or maintain a certification to a patent or patent information that
remains listed only for purposes of a first applicant’s 180-day exclusivity for its ANDA.
Once an amendment to withdraw the certification has been submitted, the
505(b)(2) application will no longer be considered to contain a paragraph IV certification
to the patent. If removal of a patent from the list results in there being no patents listed
for the listed drug(s) identified in the 505(b)(2) application, the applicant must submit
an amended certification reflecting that there are no listed patents.
(iii) Other amendments.
(A) Except as provided in paragraphs (i)(4) and (i)(6)(iii)(B) of this section:
(1) An applicant must amend a submitted certification or statement if, at any time
before the approval of the 505(b)(2) application, the applicant learns that the
submitted certification or statement is no longer accurate; and
(2) An applicant must submit an appropriate patent certification or statement
under paragraph (i)(1) of this section if, after submission of the
505(b)(2) application, a new patent is issued by the U.S. Patent and Trademark
Office that, in the opinion of the applicant and to the best of its knowledge, claims
a listed drug relied upon or that claims an approved use for such listed drug for
which information is required to be filed under section 505(b) and (c) of the Federal
Food, Drug, and Cosmetic Act and § 314.53.
(B) An applicant is not required to submit a supplement to change a submitted
certification when information on an otherwise applicable patent is submitted after the
approval of the 505(b)(2) application.
(j) Claimed exclusivity. A new drug product, upon approval, may be entitled to a period of
marketing exclusivity under the provisions of § 314.108. If an applicant believes its drug
product is entitled to a period of exclusivity, it must submit with the NDA prior to approval
the following information:
(1) A statement that the applicant is claiming exclusivity.
(2) A reference to the appropriate paragraph under § 314.108 that supports its claim.
(3) If the applicant claims exclusivity under § 314.108(b)(2), information to show that, to
the best of its knowledge or belief, a drug has not previously been approved under
45
 section 505(b) of the Federal Food, Drug, and Cosmetic Act containing any active
moiety in the drug for which the applicant is seeking approval.
(4) If the applicant claims exclusivity under § 314.108(b)(4) or (b)(5), the following
information to show that the NDA contains “new clinical investigations” that are
“essential to approval of the NDA or supplement” and were “conducted or sponsored
by the applicant:”
(i) “New clinical investigations.” A certification that to the best of the applicant’s
knowledge each of the clinical investigations included in the NDA meets the
definition of “new clinical investigation” set forth in § 314.108(a).
(ii) “Essential to approval.” A list of all published studies or publicly available reports
of clinical investigations known to the applicant through a literature search that are
relevant to the conditions for which the applicant is seeking approval, a certification
that the applicant has thoroughly searched the scientific literature and, to the best
of the applicant’s knowledge, the list is complete and accurate and, in the applicant’s
opinion, such published studies or publicly available reports do not provide a
sufficient basis for the approval of the conditions for which the applicant is seeking
approval without reference to the new clinical investigation(s) in the NDA, and an
explanation as to why the studies or reports are insufficient.
(iii) “Conducted or sponsored by.” If the applicant was the sponsor named in the Form
FDA 1571 for an IND under which the new clinical investigation(s) that is essential
to the approval of its NDA was conducted, identification of the IND by number. If
the applicant was not the sponsor of the IND under which the clinical investigation(s)
was conducted, a certification that the applicant or its predecessor in interest
provided substantial support for the clinical investigation(s) that is essential to the
approval of its NDA, and information supporting the certification. To demonstrate
“substantial support,” an applicant must either provide a certified statement from a
certified public accountant that the applicant provided 50 percent or more of the
cost of conducting the study or provide an explanation of why FDA should consider
the applicant to have conducted or sponsored the study if the applicant’s financial
contribution to the study is less than 50 percent or the applicant did not sponsor the
investigational new drug. A predecessor in interest is an entity, e.g., a corporation,
that the applicant has taken over, merged with, or purchased, or from which
the applicant has purchased all rights to the drug. Purchase of nonexclusive rights
to a clinical investigation after it is completed is not sufficient to satisfy this
definition.
(k) Financial certification or disclosure statement. The NDA must contain a financial
certification or disclosure statement or both as required by part 54 of this chapter.
(l) Format of an original NDA -
(1) Archival copy. The applicant must submit a complete archival copy of the NDA that
contains the information required under paragraphs (a) through (f) of this section. FDA
will maintain the archival copy during the review of the NDA to permit individual reviewers
to refer to information that is not contained in their particular technical sections of the
NDA, to give other agency personnel access to the NDA for official business, and
to maintain in one place a complete copy of the NDA. Except as required by paragraph
(l)(1)(i) of this section, applicants may submit the archival copy on paper or in electronic

46
 format provided that electronic submissions are made in accordance with part 11 of this
chapter.
(i) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter
(commonly referred to as the package insert or professional labeling), including all
text, tables, and figures, must be submitted to the agency in electronic format as described
in paragraph (l)(5) of this section. This requirement is in addition to the requirements
of paragraph (e)(2)(ii) of this section that copies of the formatted label and all labeling
be submitted. Submissions under this paragraph must be made in accordance with part
11 of this chapter, except for the requirements of § 11.10(a), (c) through (h), and (k),
and the corresponding requirements of § 11.30.
(ii) [Reserved]
(2) Review copy. The applicant must submit a review copy of the NDA. Each of the
technical sections, described in paragraphs (d)(1) through (6) of this section, in the review
copy is required to be separately bound with a copy of the application form required
under paragraph (a) of this section and a copy of the summary required under paragraph
(c) of this section.
(3) Field copy. The applicant must submit a field copy of the NDA that contains the technical
section described in paragraph (d)(1) of this section, a copy of the application form required
under paragraph (a) of this section, a copy of the summary required under paragraph (c) of
this section, and a certification that the field copy is a true copy of the technical section
described in paragraph (d)(1) of this section contained in the archival and review copies of
the NDA.
(4) Binding folders. The applicant may obtain from FDA sufficient folders to bind the
archival, the review, and the field copies of the NDA.
(5) Electronic format submissions. Electronic format submissions must be in a form that
FDA can process, review, and archive. FDA will periodically issue guidance on how to
provide the electronic submission (e.g., method of transmission, media, file formats,
preparation and organization of files).
Data Presentation For FDA Submission
Data presentation for FDA submission Followings are the ways to present data that facilitate
NDA review of submission.
Text exposition
Tabular presentation
1. Text exposition
Content
Most NDA submission contains enormous amount of data, which cannot be presented entirely
within the body of a document. Although the data collected for individual patient may be important,
critical judgment must be exercised in the selection of key data for presentation and discussion
within a given document. Data necessary for the development of specific thesis should be presented
within the body of a document rather than placed into remote appendix which will impede the
review. Less important data can be summarized briefly and placed in appendices. Data which add
nothing to the evaluation of safety or effectiveness of therapeutic agent, need not be presented at
all.

47
Tone
The tone of the text should be formal without being stilted. Avoid legal language on the one
hand and colloquial or informal language on the other.
Conciseness
Following are the way of making NDA submission more concise.
a. Keep the language simple and straightforward. Simple language is not unscientific; rather
it promotes clear and fast understanding. Edit out inflated language. For example,-”prior
to the initiation of the study” can be changed to much simpler “before the study began”.
b. Use acronyms and initialisms to speed up the flow of the text if they are easily recognized
and have been spelled out at first mention. Those that may be confused with another
used in the same document should be spelled out.
c. Eliminate redundancies. A careful review of the text will find many words, phrases and
even sentences that can be omitted. Sentences can often be combined by deletion of
redundant phrases, thus improving the flow of text. D. Correctness: The textual
presentation should agree with tabular data in the document; in turn, the tabular data
should agree with the data source. When lack of agreement between in-text data and
source documents is found, the reviewer will have to spend more time in evaluating the
raw data to be sure of conclusion.
Consistency
Consistent punctuation, capitalization, abbreviations, and other styling conventions are much
desired in any document.
Clarity
The FDA reviewer should be able to read an application easily and expeditiously. If a
particular document is not clear, then FDA reviewer will have the problem for understanding it.
Clarity is facilitated by careful attention to the following. Punctuation Sentence structure and
length Misplaced modifiers Parallelism.
Outline of sections and subsections
The clear relationship of one section with another is critical to the review of a document. If
no definite structure is apparent, the reviewer will become lost. The decimal system is a very
popular outlining system; it is easy to use and can be set up automatically in current word processing
software application. For e.g., 3.1.2.1.2.1.1.1 is a subsection of 3.1.2.1.2.1.1. H. Indenting : Avoid
indenting large sections of the text. Most text should be flush to the left margin with appropriate
headers to identify the section. Generally indenting with bullets are useful to break a large sections
of text.
2. Tabular presentation
In-text tables should be used to simplify the presentation and substantial reduction in text.
Information from tables should not be repeated in the text except as a part of concluding statement
about the tabular data.
Title
All tables require concise but descriptive title. Sequence of tables that are similar should
identify their differences in the title, such as at the end of the title after a colon. (Treatment related
adverse events: by Age… ,by Sex… ,by Race).
48
Data source
Every table should identify the data source contained in it. This is usually done in the footnote
to the table (data source: statistical table 23, volume XX, p. xx). The volume and page numbers
will be inserted at the end of the project.
Footnotes
Footnotes should be assigned letters, not symbols or numbers, which can be confused with
the data.
Orientation
Portrait tables are always preferable to landscape tables.
Order of data presentation
In multiple tables with similar data, present data in the same order as much as possible. If
the first column always has the active drug and the second column has the placebo or comparative
agent, then keep this order throughout the tables.
Present meaningful data together
Try to present the data that will be evaluated and compared as close together as possible
rather than scattered around the table. For e.g., if tabular data represent both evaluable and non
evaluable patients who have been either previously treated or previously untreated, place the
evaluable patient together rather than present them by previous treatment.
Upon receipt of an NDA, the FDA conducts a review of the application to determine its
completeness. Within 60 days, the FDA either accepts the filing or sends the applicant a “refusal-
to-file” letter. If the applicant receives a “refusal-to-file” letter, they can request a conference
with FDA.
Grounds for refusal to file the application include:
Form FDA 356h has not been completed.
The format of the application is not correct. One or more item is missing from the content as
described in the regulations. The manufacturing facilities are not ready for inspection. Complete
and accurate translations of all parts of the application not in English are not included.
There are no statements regarding GLP compliance for each of the non clinical studies.
There are no statements regarding compliance with IRB and informed consent regulations for
each of the clinical studies. The drug product is already covered by an approved NDA or ANDA.
At this stage FDA will send one of three possible action letters to the applicant :
One possibility is a “Not Approvable Letter,” which will list the deficiencies in the NDA
and explain why it cannot be approved.
The second possibility is an “Approvable Letter,” which indicates that ultimately the drug
product should be approved, but lists minor deficiencies and labeling changes that are needed
before an approval. Requests for commitment for post-approval studies may be included.
The third possibility is an “Approval Letter,” it states that the drug is approved. An applicant
may receive both an Approvable Letter and Approval Letter. Division director of CDER, signs
and approve a letter that the product can be legally marketed, starting on that date onwards.

49
Regulatory Agencies that are involved in drug regulation in India

Figure 1- Approval process involved in NDA

1. Drug Controller General of India

Clinical Research is regulated in India by Drug Controller General of India (DCGI). The
office of DCGI runs under CDSCO. It has main responsibility of regulating clinical trials in India.
Matters related to product approval and standards, clinical trials, introduction of new drug, and
import licenses of new drugs are handled by DCGI.
2. Drugs Technical Advisory Board (DTAB)
It has technical experts and this advice the central and state governments on all technical
matters arising out of the enforcement of drug control. No rules can be made by the central
government without consulting DTAB board.

50
3. Drugs Consultative Committee
It has central and state drug control officials as members. Its main function is to ensure the
drug control measures and enforce them uniformly over all the states.
4. Genetic Engineering approval Committee (GEAC)
It is authority to approve r-DNA pharmaceuticals products. GEAC’s role is to assess the
bio-safety/environmental safety aspect of the biotechnological product.
Some of the rules & guidelines that should be followed for regulation of
drugs in India are
Drugs and Cosmetics Act 1940 and its rules1945
Narcotic Drugs and Psychotropic Substances-1985
Drugs Price Control Order1995
Consumer ProtectionAct-1986
FactoriesAct-1948
Law of Contracts (Indian contractAct-1872)
Monopolistic & Restrictive Trade PracticesAct-1969
ICH GCPGuidelines
Schedule Y Guidelines
ICMR Guidelines
Registry of Trial
Requirements for permission of New Drugs Approval
The manufacturer / sponsor has to submit application on Form 44 for permission of New
Drugs Approval under the provisions of Drugs and Cosmetic Act 1940 and Rules 1945.
The document design is as per the International submission requirements of Common
Technical Document (CTD) and has five Modules.
Module I
Administrative/Legal Information
This module should contain documents specific to each region; for example, application
forms or the proposed label for use in the region. The content and format of this module can be
specified by the relevant regulatory authorities.
Module II
Summaries
Module 2 should begin with a general introduction to the pharmaceutical, including its
pharmacologic class, mode of action and proposed clinical use. In general, the introduction should
not exceed one page. The introduction should include proprietary name, non- proprietary name or
common name of the drug substance, company name, dosage form(s), strength(s), route of
administration, and proposed indication(s). It contains the CTD summaries for quality, safety,
efficacy information. This module is very important, as it provides detailed summaries of the
various sections of the CTD. These include: A very short introduction. Quality overall summary,

51
Non clinical overview, Clinical over view, Non clinical written and tabulated summaries for
pharmacology, pharmacokinetics, and toxicology.
Module III
Quality information (Chemical, pharmaceutical and biological)
Information on quality should be presented in the structured format described in the guidance
M4Q. This document is intended to provide guidance on the format of a registration application
for drug substances and their corresponding drug products. It contains of all of the quality
documents for the chemistry, manufacture, and controls of the drug substance and the drug product.
Module IV
Non-clinical information
Information on safety should be presented in the structured format described in the guidance
M4S. The purpose of this section is to present a critical analysis of the non-clinical data pertinent
to the safety of the medicinal product in the intended population. The analysis should consider all
relevant data, whether positive or negative, and should explain why and how the data support the
proposed indication and prescribing information. It gives final copy of all of the final nonclinical
study reports.
Module V
Clinical information
Information on efficacy should be presented in the structured format described in the guidance
M4E. It gives clinical summary including biopharmaceutics, pharmacokinetics and
pharmacodynamics, clinical pharmacology studies, clinical efficacy, clinical safety, synopses of
the individual studies and final copy of detailed clinical study reports.
Preparation of the quality information for drug submission for new drug
approval
Drug substance (name, manufacturer)
Characterization (name, manufacturer)
Physicochemical characterization
Biological characterization
Drug product (name, dosage form)
Control of drug product (name, dosage form)
Appendices
Facilities and equipment (name, manufacturer)
Safety evaluation adventitious agents (name, dosage form, manufacturer).
Application for permission to import New Drug (122-A)
a. No new drug shall be imported, except under, and in accordance with, the permission
granted by the Licensing Authority as defined in clause (b) of rule21;
b. An application for grant of permission to import a new drug shall be made in Form 44 to
the Licensing Authority, accompanied by a fee of fifty thousand rupees:
Provided further that where a subsequent application by the same applicant for that
drug, whether in modified dosage form or with new claims, is made, the fee to accompany
52
 such application shall be fifteen thousand rupees;
Provided further that any application received after one year of the grant of approval for
the import and sale of new drug, shall be accompanied by a fee of fifteen thousand
rupees and such information and data as required by Appendix 1 or Appendix 1A of
Schedule Y, as the case may be.
1. The importer of a new drug when applying for permission under sub-rule (shall
submit data as given in Appendix 1 to Schedule Y including the results of local
clinical trials carried out in accordance with the guidelines specified in that Schedule
and submit the report of such clinical trials in the format given in Appendix II to the
said Schedule:
Provided that the requirement of submitting the results of local clinical trials may
not be necessary if the drug is of such a nature that the licensing authority may, in
public interest decide to grant such permission on the basis of data available from
other countries:
Provided further that the submission of requirements relating to Animal toxicology,
reproduction studies, teratogenic studies, perinatal studies, mutagenicity and
Carcinogenicity may be modified or relaxed in case of new drugs approved and
marketed for several years in other countries if he is satisfied that there is adequate
published evidence regarding the safety of the drug, subject to the other provisions
of these rules.
2. The Licensing Authority, after being satisfied that the drug if permitted to be imported
as raw material (bulk drug substance) or as finished formulation shall be effective
and safe for use in the country, may issue an import permission in Form 45 and/or
Form 45 A, subject to the conditions stated the rein;
Provided that the Licensing Authority shall, where the data provided or generated
on the drug is inadequate, intimate the applicant in writing, and the conditions,
which shall be satisfied before permission, could be considered.
Application for approval to manufacture New Drug other than the drugs
classifiable under Schedules C and C (1) (122-B)
(a) No new drug shall be manufactured for sale unless it is approved by the Licensing
Authority as defined in clause (b) of rule21.
(b) An application for grant of approval to manufacture the new drug and its formulations
shall be made in Form 44 to the Licensing Authority as defined in clause (b) of rule 21 and shall
be accompanied by a fee of fifty thousand rupees;
Provided that where the application is for permission to import a new drug (bulk drug
substance) and grant of approval to manufacture its formulation/s, the fee to accompany such
application shall be fifty thousand rupees only;
Provided further that where a subsequent application by the same applicant for that drug,
whether in modified dosage form or with new claims, is made, the fee to accompany such
subsequent application shall be fifteen thousand rupees;
Provided further also that any application received after one year of the grant of approval
for the manufacture for sale of the new drug, shall be accompanied by a fee of fifteen thousand
rupees and such information and data as required by Appendix I or Appendix I A of Schedule Y, as
the case may be.
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 The manufacturer of a new drug under sub-rule (1) when applying for approval to the licensing
authority mentioned in the said sub-rule, shall submit data as given in Appendix I to schedule Y
including the results of clinical trials carried out in the country in accordance with the guidelines
specified in schedule Y and submit the report of such clinical trials in the format given in Appendix
II to the said schedule.
The Licensing Authority as defined in clause (b) of rule 21 after being satisfied that the drug
if approved to be manufactured as raw material (bulk drug substance) or as finished formulation
shall be effective and safe for use in the country, shall issue approval in Form 46 and/or Form 46
A, as the case may be, subject to the conditions stated therein:
Provided that the Licensing Authority shall, where the data provided or generated on the
drug is inadequate, intimate the applicant in writing, and the conditions, which shall be satisfied
before permission could be considered.
When applying for approval to manufacture of a new drug under sub-rule (1) or its
preparations to the state licensing authority, an applicant shall produce along with his application,
evidence that the drug for the manufacture of which application is made has already been approved
by the licensing authority mentioned in Rule21; Provided that the requirement of submitting the
result of local clinical trials may not be necessary if the drug is of such a nature that the licensing
authority may, in public interest decide to grant such permission on the basis of data available
from other countries;
Provided further that the submission of requirements relating to Animal toxicology,
reproduction studies, teratogenic studies, perinatal studies, mutagenicity and Carcinogenicity may
be modified or relaxed in case of new drugs approved and marketed for several years in other
countries if he is satisfied that there is adequate published evidence regarding the safety of the
drug, subject to the other provisions of these rules.
Permission to import or manufacture fixed dose combination (122-D)
An application for permission to import or manufacture fixed dose combination of two or
more drugs as defined in clause (c) of rule 122 E shall be made to the Licensing Authority as
defined in clause (b) of rule 21 in Form 44, accompanied by a fee of fifteen thousand rupees and
shall be accompanied by such information and data as is required in Appendix VI of Schedule Y.
The Licensing Authority after being satisfied that the fixed dose combination, if approved
to be imported or manufactured as finished formulation shall be effective and safe for use in the
country, shall issue permission in Form 45 or Form 46, as the case may be, subject to the conditions
stated there in; Provided that the Licensing Authority shall where the data provided or generated
on the fixed dose combination is inadequate, intimate the applicant in writing, and the conditions
which shall be satisfied before grant of approval/permission could be considered.
Application for permission to conduct clinical trials for new drug(122-D)
No clinical trial for a new drug, whether for clinical investigation or any clinical experiment
by any Institution, shall be conducted except under, and in accordance with, the permission, in
writing, of the Licensing Authority defined in clause (b) of rule21.
An application for grant of permission to conduct, -
Human clinical trials (Phase-I) on a new drug shall be made to the Licensing Authority in
Form 44 accompanied by a fee of fifty thousand rupees and such information and data as required
under Schedule Y;
Exploratory clinical trials (Phase-II) on a new drug shall be made on the basis of data emerging
54
from Phase-I trial, accompanied by a fee of twenty-five thousand rupees;
Confirmatory clinical trials (Phase-III) on a new drug shall be made on the basis of the data
emerging from Phase-II and where necessary, data emerging from Phase-I also, and shall be
accompanied by a fee of twenty-five thousand rupees:
Provided that no separate fee shall be required to be paid along with application for import/
manufacture of a new drug based on successful completion of phases of clinical trials by the
applicant.
Provided further that no fee shall be required to be paid along with the application by Central
Government or State Government institutes involved in clinical research for conducting trials for
academic or research purposes.
The Licensing Authority after being satisfied with the clinical trials, shall grant permission
in Form 45 or Form 45A or Form 46 or Form 46-A, as the case may be, subject to the conditions
stated therein:
Provided that the Licensing Authority shall, where the data provided on the clinical trials is
inadequate, intimate the applicant in writing, within six months, from the date of such intimation
or such extended period, not exceeding a further period of six months, as the Licensing Authority
may, for reasons to be recorded, in writing, permit, intimating the conditions which shall be satisfied
before permission could be considered:
Suspension or cancellation of Permission / Approval (122-DB)
If the importer or manufacturer under this Part fails to comply with any of the conditions of
the permission or approval, the Licensing Authority may, after giving an opportunity to show
because why such an order should not be passed, by an order in writing stating the reasons there
for, suspend or cancel it.
Appeal (122-DC)
Any person aggrieved by an order passed by the Licensing Authority under this Part, may
within sixty days from the date of such order, appeal to the Central Government, and the Central
Government may after such enquiry into the matter as is considered necessary, may pass such
order in relation thereto as it thinks fit.
Resources for NDA Submissions
The following resources have been gathered to provide you with the legal requirements of a
new drug application, assistance from CDER to help you meet those requirements, and internal
NDA review principles, policies and procedures.
Guidance Documents for NDAs
Guidance documents represent the Agency’s current thinking on a particular subject. These
documents are prepared for FDA review staff and applicants/sponsors to provide guidelines to the
processing, content, and evaluation/approval of applications and also to the design, production,
manufacturing, and testing of regulated products. They also establish policies intended to achieve
consistency in the Agency’s regulatory approach and establish inspection and enforcement
procedures. Because guidance are not regulations or laws, they are not enforceable, either through
administrative actions or through the courts. An alternative approach may be used if such approach
satisfies the requirements of the applicable statute, regulations, or both. For information on a
specific guidance document, please contact the originating office. For the complete list of CDER
guidance, please see the Guidance Index. For information on a specific guidance document, please
55
contact the originating office.
Guidance documents to help prepare NDAs.
❖ Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs and General
Considerations
❖ Changes to an Approved NDA or ANDA
❖ Changes to an Approved NDA or ANDA: Questions and Answers
❖ Container Closure Systems for Packaging Human Drugs and Biologics
❖ Format and Content of the Microbiology Section of an Application,
❖ Format and Content of the Clinical and Statistical Sections of an Application
❖ Summary for New Drug and Antibiotic Applications—Format and Content of the Summary
for New Drug and Antibiotic Applications
❖ Formatting, Assembling and Submitting New Drug and Antibiotic Applications,
❖ GUIDELINE FOR SUBMITTING SUPPORTING DOCUMENTATION IN DRUG
APPLICATIONS FOR THE MANUFACTURE OF DRUG PRODUCTS
❖ NDAs: Impurities in Drug Substances
❖ Format and Content of the Human Pharmacokinetics and Bioavailability Section of an
Application
❖ Format and Content of the Nonclinical Pharmacology/Toxicology Section of an Application
❖ Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products
❖ Drug Master Files: Guidelines
❖ FDA IND, NDA, ANDA, or Drug Master File Binders
❖ PET Drug Applications - Content and Format for NDAs and ANDAs — 2011
Laws, Regulations, Policies and Procedures
The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established
by the Agency to protect the consumer’s health, safety, and pocketbook. The Federal Food, Drug,
and Cosmetic Act is the basic food and drug law of the U.S. With numerous amendments, it is the
most extensive law of its kind in the world. The law is intended to assure consumers that foods are
pure and wholesome, safe to eat, and produced under sanitary conditions; that drugs and devices are
safe and effective for their intended uses; that cosmetics are safe and made from appropriate
ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.
Code of Federal Regulations (CFR)
The final regulations published in the Federal Register (daily published record of proposed
rules, final rules, meeting notices, etc.) are collected in the CFR. The CFR is divided into 50
titles which represent broad areas subject to Federal regulations. The FDA’s portion of
the CFR interprets the Federal Food, Drug and Cosmetic Act and related statutes. Section 21 of
the CFR contains all regulations pertaining to food and drugs. The regulations document all actions
of all drug sponsors that are required under Federal law.
21CFR Part 314 - Applications for FDA Approval to Market a New Drug or an Antibiotic
Drug.

56
CDER’s Manual of Policies and Procedures (MaPPs)
These documents are approved instructions for internal practices and procedures followed
by CDER staff to help standardize the new drug review process and other activities. MaPPs define
external activities as well. All MaPPs are available for the public to review to get a better
understanding of office policies, definitions, staff responsibilities and procedures.
MaPPS of particular interest to NDA applicants
❖ Review of the Same Supplemental Change to More than One NDA or ANDA in More Than
One Review Division
❖ NDAs and BLAs: Filing Review Issues
❖ Action Packages for NDAs and Efficacy Supplements
❖ Refusal to Accept Application for Filing from Applicants in Arrears
❖ Requesting and Accepting Non-Archivable Electronic Material for CDER Applications
Prescription Drug User Fee Act (PDUFA)
On November 21, 1997, The President signed the Food and Drug Administration
Modernization Act of 1997. This legislation includes authorization for FDA to continue to collect
three types of user fees from applicants who submit certain new drug and biological product
applications. FDA was first authorized to collect user fees under the Prescription Drug User Fee
Act (PDUFA) of 1992.
❖ Prescription Drug User Fee Act Related Documents
NDA Forms and Electronic Submissions
❖ Form FDA-356h. Application to Market a New Drug, Biologic, or An Antibiotic Drug for
Human Use
❖ Form FDA-356h instructions
❖ Form FDA-3397. User Fee Cover Sheet
❖ Form FDA-3331. New Drug Application Field Report
❖ Guidance Documents for Electronic Submissions
❖ For more information on electronic submissions, see Electronic Regulatory Submissions
and Review Helpful Links.
Advisory Committees
Advisory committees provide independent advice and recommendations to the FDA on
scientific and technical matters related to the development and evaluation of products regulated
by the Agency. CDER requests advice from advisory committees on a variety of matters, including
various aspects of clinical investigations and applications for marketing approval of drug products.
Committee members are scientific experts such as physician-researchers and statisticians, as well
as representatives of the public, including patients. Although the committees provide
recommendations to the Agency, final decisions are made by FDA.
❖ FDA Advisory Committees
❖ CDER Advisory Committees
❖ CFR 21 Part 14 Public Hearing before a Public Advisory Committee. Detailed description
of advisory committees from the Code of Federal Regulations.
❖ Guidance for Industry: Advisory Committees. Includes information on membership, conflict
of interest, scheduling, and action on recommendations.

57
❖ Advisory Committee Meeting Calendar. Several dates have been set aside by CDER advisory
committees for possible future meetings. The subject matter and location of the meetings (if
they are held) will be published in the Federal Register in the month prior to the meeting
date.
Approval of new drug in India
When a company in India wants to manufacture/ import a new drug it has to apply to seek
permission from the licensing authority (DCGI) by filing in Form 44 also submitting the data as
given in Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945. In order to prove its
efficacy and safety in Indian population it has to conduct clinical trials in accordance with the
guidelines specified in Schedule Y and submit the report of such clinical trials in specified format.
But a provision is there in Rule- 122A of Drugs and Cosmetics Act 1940 and Rules 1945
that the licensing authority may waive certain trails if he considers that in the interest of public
health, he may grant permission for import of new drugs basing on the data of the trials done in
other countries. Similarly, there is another provision in Rule- 122A which says that the clinical
trials may be waived in the case of new drugs which are approved and being used for several years
in other countries.
Section 2.4 (a) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says for
those drug substances which are discovered in India all phases of clinical trials are required.
Section 2.4 (b) of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says that
for those drug substances which are discovered in countries other than India; the applicant should
submit the data available from other countries and the licensing authority may require him to
repeat all the studies or permit him to proceed from Phase III clinical trials.
Section 2.8 of Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says that the
licensing authority may require pharmacokinetic studies (Bioequivalence studies) first to show
that the data generated in Indian population is equal to data generated abroad and then require
him to proceed with Phase III trials.
In summary, the exact requirements of Clinical trials may change from case to case and
depend on the extent to which licensing authority is satisfied about its safety and efficacy.
The process of approval of new drug in India is a very complicated process, which should
meet necessary requirements along with NDA to FDA. The need of the present work is to study
and document the requirements for the process of approval of new drug in India with emphasis on
clinical trials as per Drugs Control department, Government of India.

58
 Figure 2: Pictorial representation drug approval process in India

Abbreviated New Drug Application (ANDA)

Background
An abbreviated new drug application (ANDA) contains data which is submitted to FDA for
the review and potential approval of a generic drug product. Once approved, an applicant may
manufacture and market the generic drug product to provide a safe, effective, lower cost alternative
to the brand-name drug it references.
A generic drug product is one that is comparable to an innovator drug product in dosage
form, strength, route of administration, quality, performance characteristics, and intended use.
All approved products, both innovator and generic, are listed in FDA’s Approved Drug Products
with Therapeutic Equivalence Evaluations (Orange Book).
59
 Generic drug applications are termed “abbreviated” because they are generally not required
to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.
Instead, generic applicants must scientifically demonstrate that their product is performs in the
same manner as the innovator drug. One-way applicants demonstrate that a generic product
performs in the same way as the innovator drug is to measure the time it takes the generic drug to
reach the bloodstream in healthy volunteers. This demonstration of “bioequivalence” gives the
rate of absorption, or bio-availability, of the generic drug, which can then be compared to that of
the innovator drug. To be approved by FDA, the generic version must deliver the same amount of
active ingredients into a patient’s bloodstream in the same amount of time as the innovator drug.
The “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the
Hatch-Waxman Amendments, established bioequivalence as the basis for approving generic copies
of drug products. These Amendments permit FDA to approve applications to market generic
versions of brand-name drugs without repeating costly and duplicative clinical trials to establish
safety and efficacy. Under the Hatch-Waxman Amendments, brand-name companies gained patent
term extension to account for the time the patented product is under review by FDA and also
gained certain periods of marketing exclusivity. In addition to the ANDA approval pathway,
generic drug companies gained the ability to challenge patents in court prior to marketing as well
as 180-day generic drug exclusivity.
Through an Abbreviated new drug application (ANDA) process, applicant may get FDA
approval for a generic drug without conducting clinical trials if the drug is bioequivalent to the
branded (innovator) drug. All generic drugs approved by FDA have the same high quality, strength,
purity and stability as brand name drugs.
Types of ANDA:
Para I: A Para I filing for the launch of generic drug is made when the innovator has not
made the required information in the Orange book.
Para II: A Para II filing is made when the drug is already off patent.
Para III: A Para III filing is made when the applicant does not have any plans to sell the
generic drug until the original drug is off patent.
Para IV: A Para IV filing for the launch of generic drug is made when the applicant believes
its product or the use of its product does not infringe on the innovator’s patents or where the
applicant believes such patents are not valid or enforceable.

Figure 3 -Types of ANDA

60
 An ANDA certified under paragraphs I or II is approved immediately after meeting all
applicable regulatory and scientific (efficacy, safety and bioequivalence) requirements. This means
that the generic drugs manufacturer may get immediate approval for manufacturing the generic
versions of the branded drugs upon filing an ANDA if, the patent information on the branded drug
has not been filed by the branded drug manufacturer or if the patent for the branded drug has
expired. A Para III filing is made when the ANDA applicant does not have any plans to sell the
generic drug until the original drug is off patent. In case of Para III the application is processed for
approval, however its approval status depends upon the product’s patent expiry. ANDA approval
under Para III certification is made effective from the date of patent expiration.
An ANDA applicant filing a paragraph IV certification must notify the proprietor of the patent.
The patent holder may bring a patent infringement suit within 45 days of receiving such notification.
If the patent owner timely brings a patent infringement charge against the ANDA applicant, then
the USFDA suspends the approval of the ANDA until the date of the court’s decision that the
listed drug patent is either invalid or not infringed the date on which the listed drug patent expires,
if the court finds the listed drug’s patent is infringed; or the date that is 30 months from the date
the owner of the listed drug’s patent received notice of the filing of a Paragraph IV certification.
(Subject to modification by the court). This means that for 30 months from the date of receipt of
notice of Para VI filing, no ANDA can be approved. In other words, once the branded drug company
indicates its intent to begin a patent infringement suit against the generic company as a result of
the paragraph IV filing, the USFDA is prohibited from approving the drug in question for thirty
months or until such time that the patent is found to be invalid or not infringed. If, prior to the
expiration of thirty months, the court holds that the patent is invalid or would not be infringed,
then the USFDA approves the ANDA when that decision occurs. Conversely, if the court holds
that the patent is valid and would be infringed by the product proposed in the ANDA prior to the
expiration of thirty months, then the USFDA does not approve the ANDA until the patent expires.
FDA Review Procedure:
Drugs intended for human use are evaluated by FDA’s Center for Drug Evaluation and
Research (CDER) to ensure that drugs marketed in the United States are safe and effective.
Biological products are evaluated by FDA’s Center for Biologics Evaluation and Research.
1. As a part of the review process FDA will send the application of the applicant to OGD/
CDER review team for the approval.
2. If the submitted application is not complete or any deficiencies are identified, then “refuse
to file letter” is issued by the OGD/CDER to the applicant.
3. In case the application has found complete without any deficiencies then it’s accepted &
application is then sent to the internal review team for the identification of Bio-Equivalence,
Chemistry/Microbiology, Plant inspection & Labeling review issues.
4. If any pending results are found in the application, Bio-Equivalence deficiency letter, &
pending satisfactory results are issued accordingly to the applicant.
5. Once the ANDA submission is complete and acceptable without any further queries, the
applicant finally receives FDA approval letter.
Resources for ANDA Submissions
The following resources provide ANDA applicants with the statutory and regulatory
requirements of an ANDA application, assistance from CDER to help you meet those requirements,
and internal ANDA review principles, policies, and procedures. Summary tables, application forms,

61
 Figure 4- Approval process of ANDA

and other ANDA submission resources are available in ANDA Forms & Submission Requirements.
Guidance Documents for ANDAs
Guidance documents represent the Agency’s current thinking on a particular topic. These
documents provide guidelines for the content, evaluation, and ultimate approval of applications
and also to the design, production, manufacturing, and testing of regulated products for FDA
review staff, applicants, and ANDA holders.
❖ Generic Drugs Guidance (Search “Generics” under topics)
❖ Biopharmaceutics Guidance (Search “Biopharmaceutics” under topics)
❖ Product-Specific Guidance for Generic Drug Development
Laws, Regulations, Policies, and Procedures
The Federal Food, Drug, and Cosmetic Act is the basic food and drug law of the United
62
States. The law is intended to assure consumers that foods are pure and wholesome, safe to eat,
and produced under sanitary conditions; that drugs and devices are safe and effective for their
intended uses; that cosmetics are safe and made from appropriate ingredients; and that all labeling
and packaging is truthful, informative, and not deceptive.
Code of Federal Regulations
The final regulations published in the Federal Register (a daily published record of proposed
rules, final rules, meeting notices, etc.) are collected in the Code of Federal
Regulations (CFR). Section 21 of the CFR contains most of the regulations pertaining to food
and drugs. The regulations document most actions of all drug applicants that are required under
Federal law. The following regulations directly apply to the ANDA process:
21CFR Part 314: Applications for FDA Approval to Market a New Drug
21CFR Part 320: Bioavailability and Bioequivalence Requirements
Manual of Policies and Procedures
CDER’s Manual of Policies and Procedures (MAPPs) document internal practices and
procedures followed by CDER staff to help standardize the drug review process and other activities,
both internal and external. Chapter 5200 covers generic drugs processes and activities

Changes to an approved NDA / ANDA

Background
This guidance provides recommendations to holders of NDAs and ANDAs who intend to
make post approval changes in accordance with section 506A of the Federal Food, Drug, and
Cosmetic Act and 314.70 (21 CFR 314.70). It supersedes the guidance of the same title published
November 1999. Recommendations are provided for post approval changes in
1. Components and composition
2. Manufacturing sites
3. Manufacturing process
4. Specifications
5. Container closure system, and
6. Labeling, as well as
7. Miscellaneous changes and
8. Multiple related changes.
Guidance prepare
prepared by under the direction of the Chemistry, Manufacturing and Controls Coordinating
Committee in the Center for Drug Evaluation and Research (CDER) at the FDA.
Modernization Act
On November 21, 1997, the President signed the FDA Modernization Act of 1997.
Section 116 of the Modernization Act
Amended the Act by adding section 506A, which provides requirements for making and

63
reporting manufacturing changes to an approved application and for distributing a drug product
made with such changes.
The FDA has revised its regulations
on supplements and other changes to an approved application (21 CFR 314.70) to conform
to section 506 A of the Act.
To assess the effect of the change on the identity, strength (e.g., assay, content uniformity),
Quality (e.g., physical, chemical, and biological properties), Purity (e.g., impurities and degradation
products), or Potency (e.g., biological activity, bio-availability, bioequivalence) of a drug product
as these factors may relate to the safety or effectiveness of the drug product. v CDER has published
guidance, including the SUPAC (scale-up and post approval changes) guidance, that provide
recommendations on reporting categories. Reporting categories: This guidance does not provide
for components and composition changes. Section 506A of the Act and 314.70(c) provide for two
types of changes-being affected supplements while previously there was only one type.
A. Major change
Major change is a change that has a substantial potential to have an adverse effect on the
identity, strength, quality, purity, or potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product
Prior Approval Supplement: An applicant may ask FDA to expedite its review of a prior
approval supplement for public health reasons (e.g., drug shortage)
B. Moderate change
Moderate change is a change that has a moderate potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product as these factors may relate to the
safety or effectiveness of the drug product. There are two types of moderate change. (314.70(c)(6)).
Supplement - Changes Being Affected in 30 Days: requires the submission of a supplement to
FDA at least 30 days before the distribution of the drug product made using the change. }
Supplement - Changes Being Affected: FDA may identify certain moderate changes for which
distribution can occur when FDA receives the supplement.
C. Minor change
Minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency
of the drug product as these factors may relate to the safety or effectiveness of the drug product.
The applicant must describe minor changes in its next Annual Report
a. Editorial changes: in previously submitted information (e.g., correction of spelling or
typographical errors, reformatting of batch records), (314.70(a)(1)).
b. Supplement or annual report: must include a list of all changes. list must be provided
in the cover letter (314.70(a)(6)). In annual reports, the list should be included in the
summary section (314.81(b)(2)(i)).
c. An applicant making a change: to an approved application under section 506A of the
Act must also conform to other applicable laws and regulations, including current good
manufacturing practice (CGMP) requirements of the Act (21 U.S.C. 351(a)(2)(B))
d. Code of Federal Regulations: (e.g., 21 CFR parts 210, 211, 314). Labeling changes
under 314.70(c)(6)(iii) must include 12 copies of the final printed labeling (314.70(c)(1)).
In accordance with 314.70(a)(4), any labeling change implemented in accordance with
314.70(b) or (c).
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Assessment of the Effects of the Change
The holder of an approved application under section 505 of the Act manufacturing change.
1. Conformance to Specifications
A specification is a quality standard (i.e., tests, analytical procedures, and acceptance criteria)
provided in an approved application to confirm the quality of drug substances, drug products,
intermediates, raw materials, reagents, components, in-process materials, container closure systems,
and other materials used in the production of drug product. “Acceptance criteria are numerical
limits, ranges, or other criteria for the tests described.” Conformance to a specification means
that the 8 material, when tested according to the analytical procedures listed in the specification,
will meet the listed acceptance criteria.
2. Additional Testing
material affected by manufacturing changes that the applicant performs additional testing,
when appropriate, to assess whether the identity, strength, quality, purity, or potency of the drug
product as these factors may relate to the safety or effectiveness of the drug product have been or
will be affected.
Evaluation of any changes in the chemical, physical, microbiological, biological, bio-
availability, or stability profiles. Type of manufacturing change, the type of drug substance and
the effect of the change on the quality of the drug product. For example:
a. Evaluation of changes in the impurity: Toxicology tests to qualify a new impurity.
b. Evaluation of the hardness or friability: Tablet B. Equivalence: When testing is
performed, the applicant should usually assess the extent to which the manufacturing
change has affected the identity, strength, quality, purity, and potency of the drug product.
Equivalent does not necessarily mean identical. Equivalence may also relate to
maintenance of a quality characteristic (e.g., stability) rather than a single performance
of a test.
c. Adverse Effect: Some manufacturing changes have an adverse effect on the identity,
strength, quality, purity, or potency of the drug product. If an assessment indicates that
a change FDA recommends that the change be submitted in a prior approval supplement
regardless of the recommended reporting category for the change. For example, a process
change recommended for a changes-being-effected-in-30days
d. Changes in the qualitative or quantitative formulation: including inactive ingredients,
as provided in the approved application, are considered major changes requiring a prior
approval supplement, unless exempted by regulation or guidance (314.70(b)(2)(i)).
e. The deletion or reduction of an ingredient: Intended to affect only the color of the
drug product may be reported in an annual report (314.70(d)(2)(ii)).
3. Guidance on changes in components and composition
that may be submitted in a changes-being-effected supplement or annual report is not included in
this document because of the complexity of the recommendations, but may be covered in one or
more guidance documents describing post approval changes (e.g., SUPAC documents).
A. General Considerations
CDER must be notified when a manufacturer changes to a manufacturing site that is different
from those specified in the approved application (314.70(a)). Sites can include those used by an
applicant to
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 1. Manufacture or process drug products: in-process materials, drug substances, or drug
substance intermediates,
2. Package drug products,
3. Label drug products, and
4. Test components, drug product containers, closures, packaging materials, in-process
materials, or drug products.
a. Testing sites: Include those performing physical, chemical, biological, and
microbiological testing to monitor, accept, or reject materials, as well as those performing
stability testing.
b. FDA recommends: That a move to a different manufacturing site, when it is a type of
site routinely subject to FDA inspection, be submitted as a prior approval supplement if
the site does not have a satisfactory CGMP inspection for the type of operation being
moved.
Major Changes
Following are examples of changes.
1. Changes that may affect the controlled (or modified) release,
2. Changes that may affect drug product sterility assurance including,
a. Changes in the sterilization method.
These include changes from sterile filtered or aseptic processing to terminal sterilization.
b. Addition to an aseptic processing line of new equipment made of different materials
c. Replacing a Class 100 aseptic fill area with a barrier system or isolator for aseptic filling.
d. Changes from bioburden-based terminal sterilization to the use of an overkill process,
e. Changes in materials or pore size rating of filters used in aseptic processing.
3. Manufacturing process or technology
Drug product:
Dry to wet granulation
Drug substance:
Filtration to centrifugation & Change in the route of synthesis of a drug substance.
Addition of an ink code imprint or in the ink used for an existing imprint code when the ink
as changed is not currently used on CDER-approved drug products
Specifications (i.e., tests, analytical procedures, and acceptance criteria) are the quality
standards provided in an approved application to confirm the quality of drug substances, drug
products, intermediates, raw materials, reagents, components, in- process materials, container
closure systems, and other materials used in the production of a drug substance or drug product.
The recommendations in this section also apply to specifications associated with sterility assurance.
The potential for adverse effect on the identity, strength, quality, purity, or potency of a drug
product as these factors may relate to the safety or effectiveness of the drug product when making
a change to or in the container closure system is generally dependent on the route of administration
of the drug product, performance of the container closure system, and the likelihood of interaction

66
between the packaging component and the dosage form. In some cases, there may be a substantial
potential for adverse effect, regardless of direct drug product testing for conformance with the
approved specification.
A change to or in a packaging component will often result in a new or revised specification
for the packaging component. This situation does not have to be considered a multiple related
change. Only the reporting category for the packaging change needs to be considered.
A change in a drug’s labeling includes changes in one of the following:
Package insert
Package labeling
Container label
All promotional labeling and advertising must be promptly revised to be consistent with
any labeling change(s) implemented. In addition, “all labeling changes for ANDA drug products
must be consistent with section 505(j) of the Act.”
Multiple related changes involve various combinations of individual changes. If an applicant
has multiple related changes that fall into different recommended reporting categories, “CDER
recommends that the submission be in accordance with the reporting category for the individual
changes.”
As this is simply a summary of the guidance document, we only touched on the “general
considerations” that are provided. FDA also provides numerous examples of each type of change
that is considered to be major, moderate, and minor.
Overview of regulatory authorities of India, United States, European
Union, Australia, Japan, Canada (Organization structure and types

67
 02 Regulatory authorities and agencies

of applications)
Background
Regulatory affairs in pharmaceutical industry aim at the protection of human health. People
and government spent money on drugs because of the role they can play in saving lives, restoring
health, preventing diseases and stopping epidemics. But, in order to do so, drug must be safe,
effective and of good quality. Since the purpose of drug is to diagnose, prevent or treat diseases or
ailments in humans, they are products intimately linked with the advances in research and
regulation. The pharmaceutical industry, while pursuing an international market, is obliged to
comply with national regulations. So, in this review article, an overview of few drug regulatory
agencies of four countries: India, USA, Europe& Japan is covered. Regulatory agencies and
organizations play a vital role to meet the requirements of legal procedures related to drug
development process in a country. Every country has its own regulatory authority, which is
responsible to enforce the rules and regulations and issue the guidelines to regulate the drug
development, licensing& registration.

Sr. No Country Authority

1 India CDSCO
2 USA USFDA
3 European Union EMEA
4 Australia TGA
5 Japan MHLW
6 CANADA HEALTH CANADA

Drug Regulatory Agencies in India

India has emerged as one of the leading markets for pharmaceutical products. Increase in
the private health care infrastructure, widening rural markets, and inclusion of newer technologies
have placed health care as an in dependent sector in India. With privatization of health care, the
medical devices sector is growing too.
In order to regulate the import, manufacture, distribution and sale of drugs and cosmetics,
the Drugs and Cosmetics Act,1940 (“D&C,Act”) was introduced in India in 1940. However, no
separate regulation has been enacted for regulating the import, manufacture, distribution or sale
of medical devices in India till date by the Government of India. Drugs and Health is in concurrent
list of Indian Constitution. It is governed by both Centre and State Governments under the Drugs
& Cosmetics Act, 1940.
Main Bodies
Central Drug Standard Control
Organization (CDSCO) Ministry of Health & Family Welfare (MHFW)
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 Indian Council of Medical
Research (ICMR) Indian
Pharmaceutical Association (IPA) Drug Technical Advisory Board (DTAB)
Central Drug Testing Laboratory (CDTL) Indian Pharmacopoeia Commission (IPC)
National Pharmaceutical Pricing Authority (NPPA)
Functions undertaken by Central Government Statutory function laying down standards of
drugs, cosmetics, diagnostics and devices. Laying down regulatory measures, amendments to Act
sand Rules. To regulate market authorization of new drugs. To regulate clinical research in India
to approve licenses to manufacture certain categories of drugs as Central License Approving
Authority i.e. for Blood Banks, Large Volume Parenteral and Vaccines & Sera. To regulate the
standards of imported drugs. Work relating to the Drugs Technical Advisory Board (DTAB) and
Drugs Consultative Committee (DCC). Testing of drugs by Central Drugs Labs. Publication of
Indian Pharmacopoeia.
Central Drugs Standard Control Organization (CDSCO)
In India, the Central Drugs Standard Control Organization (CDSCO) is the main regulatory
body currently regulating import, sale and manufacture of medical devices which have been notified
as drugs by virtue of Section 3(b) (IV) of the D&C Act. The CDSCO lays down standards of
drugs, cosmetics, diagnostics and devices and issues licenses to drug manufacturers and importers.
It also lays down regulatory measures, amendments to Act sand Rules and regulates market
69
authorization of new drugs, clinical research in India and standards of imported drugs etc.
Head quartered in New Delhi, the CDSCO is India’s main regulatory body for pharmaceuticals
and medical device sand Within the CDSCO, the Drug Controller General of India (DCGI) is
responsible for the regulation of pharmaceuticals and medical devices. The DCGI is advised by
the Drug Technical Advisory Board (DTAB) and the Drug Consultative Committee (DCC).
Licensing and classification of medical devices are handled by the Central Licensing Approval
Authority (CLAA). The CLAA is also responsible for setting and enforcing safety standards,
appointing notified bodies to oversee conformity assessment, conducting post- market surveillance
and issuing warning sander calls for adverse events. The CDSCO establishes safety, efficacy, and
quality standards for pharmaceuticals and medical devices. It publishes and updates the Indian
Pharmacopeia, a list of regulated pharmaceuticals and devices. For all drug and device applications,
the CDSCO appoints notified bodies to perform conformity assessment procedures, including
testing, in order to ensure compliance with their standards. The CDSCO is also divided into
several zonal offices which do pre-licensing and post-licensing inspections, post-market
surveillance, and recalls when necessary.
In addition to its regulatory functions, the CDSCO offers technical guidance, trains regulatory
officials and analysts, and monitors adverse events. The CDSCO works with the World Health
Organization to promote Good Manufacturing Practice (GMP) and international regulatory
harmony.
National Institute of Health and Family Welfare (NIHFW)
NIHFW is an Apex Technical Institute, funded by Ministry of Health and Family Welfare,
for promotion of health and family welfare programmers in the country through education, training,
research, evaluation, consultancy and specialized services. The NIHFW was established on March
9, 1977 by a merger of the National Institute of Health Administration and Education (NIHAE)
with the National Institute of Family Planning (NIFP).
List of Governing Body Members of NIHFW 18 members
1 Chairman (ex-officio)
1 Vice Chairman (ex-officio) 9 Member (ex-officio)
6 Member
1 Member Secretary (ex-officio)
Activities and Responsibilities
Measuring weight of children to assess the nutritional status. Assessment of diseases like
level of anemia. Testing of foodmaterial like cooking salt for level, iodine. To release fund on the
advice of the Ministry. It is responsible for all governmental programs relating to family planning
in India.
Drug technical advisory board(DTAB)
The Central Government constitute a Board (to be called the Drugs Technical Advisory
Board) to advise the Central Government and the State Governments on technical matters arising
out of the administration of D&C, Act 1940 List of Governing Body Members of NIHFW:18
Members
10ex-officioMembers
5NominatedMembers

70
 5 Elected Members
Activities and responsibilities
Its advices matter related to Drugs. The nominated and elected members of the Board shall
hold office for three years, but shall be eligible for re-nomination and re-election. The Board may,
subject to the previous approval of the Central Government, make bye-laws fixing a quorum and
regulating its own procedure.
Central drug testing laboratory (CDTL)
The central drug laboratory, Kolkata is national statutory laboratory of the Government of
India for quality control of drug and cosmetic and established under the D&C act, 1940. Oldest
quality control laboratory of the drug control authorities in India. Function under the director
general of Health Services in the Ministry of Health and Family Welfare.
Composition
Indian Pharmacopoeia Commission (IPC) General Body 19Members
Governing Body 10 Members Scientific Body 23 Experts
CIPL Lab IPC Secretariat Indian Pharmacopoeia was prepared by Indian Pharmacopoeia
Commission (IPC)
Activities and responsibilities
Development of comprehensive monographs. Accord priority to monographs of drugs
included in the national Essential Drug List and their dosage forms. Preparation of mono graph
for products that have normally been in the market for not less than 2 years. Collaborate with
pharmacopoeias like the BP, USP, JP and International Pharmacopoeia with a view to harmonizing
with global standards.

Drug regulatory agencies in USA

USFDA
The Food and Drug Administration (FDA) National Institutes of Health (NIH) Centers for
Disease Control and Prevention Department of Health and Human Services (DHHS) Fed World -
US Government Information National Centre for Complementary and Alternative Medicine
(NCCAM) National Centre for Infectious Diseases (NCID) National Library of Medicine National
Science Foundation Office of Disease Prevention.
The Food and Drug Administration (FDA) is an agency within the U.S. Department of Health
and Human Services. It consists of six product centers, one research Centre, and two offices.
FDA’s responsibilities extend to the 50 United States, the District of Columbia, Puerto Rico,
Guam, the Virgin Islands, American Samoa, and other U.S. territories and possessions. Food and
Drug Administration 10903 New Hampshire Ave Silver Spring, MD20993-0002
The Food and Drug Modernization Act states that the FDA has 4 roles:
To promote health by reviewing research and approving new products.
To ensure foods and drugs are safe and properly labelled.
To work with other nations to “reduce the burden of regulation”.
To cooperate with scientific expertsand consumers to effectively carry out these obligations
71
The FDA is led by the Commissioner of Food and Drugs, who is appointed by the President and
confirmed by the Senate.
FDA is responsible for Protecting the public health by assuring that foods are safe, wholesome,
sanitary and properly labelled; Assuring human and veterinary drugs, and vaccines and other
biological products and medical devices intended for human use are safe and effective Protecting
the public from electronic product radiation Assuring cosmetic sand dietary supplements are safe
and properly labelled Regulating tobacco products Advancing the public health by helping to
speed product innovations Helping the public get the accurate science-based information they
need to use medicines, devices, and foods to improve their health Initiation of a Recall. Includes
voluntary, FDA requested, and FDA mandated.
FDA is responsible for: protecting the public health by assuring the safety, effectiveness,
and security of human and veterinary drugs, vaccines and other biological products, medical
devices, our nation’s food supply, cosmetics, dietary supplements, and products that give off
radiation regulating tobacco products advancing the public health by helping to speed product
innovations helping the public get the accurate, science-based information they need to use
medicines and foods to improve their health. FDA is responsible for Protecting the public health
by assuring that foods are safe, wholesome, sanitary and properly labelled; vaccines and other
biological products and medical devices intended for human use are safe and effective. Protecting
the public from electronic product radiation Assuring cosmetics and dietary supplements are safe
and properly labelled Regulating tobacco products Advancing the public health by helping to
speed product innovations Helping the public get the accurate science-based information they
need to use medicines, devices, and foods to improve their health Initiation of a Recall. Includes
voluntary, FDA requested and FDA mandated.

Drug regulatory agencies in Europe

European Medicines Agency (EMA)
EMAisa European agency for the evaluation of medicinal product. EMA was setup in1995.
From 1995 to 2004, EMA was known as European agency for the evaluation of medicinal product.
The European Medicines Agency (EMA) is a decentralized body of the European Union, located
in London Mission: to foster scientific excellence in evaluation and supervision of medicines.
Activities of EMA
Provides independent, science-based recommendations on the quality, safety and efficacy
of medicines. Applies efficient and transparent evaluation procedures to help bring new medicines
to the market. Implements measures for continuously supervising the quality, safety and efficacy
of authorized medicines. Provides scientific advice to stimulate the development and improve the
availability of innovative new medicines. Recommend safe limits for residues of veterinary
medicines used in food-producing animals. Publishes impartial and comprehensible information
about medicine sand their use; develops best practice for medicines evaluation and supervision in
Europe, and contributes alongside the Member States and the European Commission to the
harmonization of regulatory standards at the international level. European Directorate for the
Quality of Medicines & Health Care the EDQM (Council of Europe) is a key European Organization
involved in Harmonization & Co-ordination of Standardization, Regulation & Quality Control of
Medicines, Blood Transfusion, Organ Transplantation, Pharmaceutical sand Pharmaceutical Care.
In 1996 The European Directorate for the Quality of Medicines (EDQM) is created. EMA is a
72
European agency for the evaluation of medicinal product. EMA was set up in 1995. From 1995 to
2004, EMA was known as European agency for the evaluation of medicinal product. The European
Medicines Agency (EMA) is a decentralized body of the European Union, located in London
Mission: to foster scientific excellence in evaluation and supervision of medicines. Office of
executive director Executive director Legal service Senior medical officer Internal audit Information
and communicate ion veterinary medicines and product data management Patient health protection
Human medicines development and evaluation

Drug regulatory agencies in japan

Ministry of Health, Labor, and Welfare (MHLW)
The Ministry of Health, Labour, and Welfare (MHLW) was established by a merger of the
Ministry of Health and Welfare (MHW) and the Ministry of Labour, on January 6,2001. The
MHLW, which was originally established in 1938, has been in charge of the improvement and
promotion of social welfare, social security and public health, and the new organization has the
same tasks. It consists of the ministry proper, affiliated institutions, councils, local branches, and
an external organization.
MHLW Social insurance agency Ministry proper Minister’s secretariat Heath policy bureau
Heath service bureau PFSB Social welfare & war victim’s relief bureau Health and welfare bureau
for elderly Equal employment children & family bureau Insurance bureau Pension bureau Director
general for policy planning. Services for persons with disabilities Social Security: Pension systems
that will ensure income in elderly age Long term insurance to provide nursing care services Public
assistance systems that guarantee minimum standards
Function of MHLW
Public Hygiene: Appropriate medical services for diseases & injuries ensuring the safety of
food, Water and medical supplies Research into health science in order to make technological
advances Maternal and child health Job Security: Promotion of employment Labor of elderly
people Employment of persons with disabilities Management of the employment insurance system
Human Resources Development: Promotion of human resources development that reacts to
changes in the industrial system Encouragement of worker’s skill development under their own
initiative Development of skilled human resources that support industrial progress

Regulatory process for drug in Canada

The exhibit shows the steps in the regulatory process for drugs in Canada, from pre-market
to post-market. The pre-market part of the process starts with pre- clinical studies.
The steps are
Pre-clinical studies
Clinical trials
Regulatory product submission
Submission review
Market authorization decision

73
 Public access
Surveillance, inspection, and investigation
The post-market part of the process begins with surveillance, inspection, and investigation
when a drug has been made accessible to the public.
Submission type and their description
Cosmetic
All cosmetics sold in Canada must be safe to use and must not pose any health risk. They
must meet the requirements of the Food and Drugs Act and the Cosmetic Regulations.
Under the Food and Drugs Act, a cosmetic includes “any substance or mixture of substances,
manufactured, sold or represented for use in cleansing, improving or altering the complexion,
skin, hair or teeth and includes deodorants and perfumes.” This includes cosmetics used by
professional esthetic services, bulk institutional products (such as hand soap in school rest rooms),
as well as “handmade” cosmetics sold at craft sales or home- based businesses.
The Cosmetic Regulations and the Food and Drugs Act require that cosmetics sold in Canada
be manufactured, prepared, preserved, packed and stored under sanitary conditions. The
manufacturer and importer must notify Health Canada that it is selling the product and provide a
list of the product’s ingredients.
Definitions
1. cosmetic (Section 2 of the Food and Drugs Act)
any substance or mixture of substances manufactured, sold or represented for use in cleaning,
improving or altering the complexion, skin, hair or teeth, and includes deodorants and perfumes.
2. drug (Section 2 of the Food and Drugs Act)
Includes any substance or mixture of substances manufactured, sold or represented for use in
(a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal
physical state, or its symptoms, in human beings or animals,
(b) restoring, correcting or modifying organic functions in human beings or animals, or
(c) disinfection in premises in which food is manufactured, prepared or kept;
3. natural health product (Section 1 of the Natural Health Products
Regulations pursuant to the Food and Drugs Act)
A subset of drugs pertaining to medicinal ingredients of natural origin, defined in the Natural
Health Products Regulations as “a substance set out in Schedule 1 or a combination of substances
in which all the medicinal ingredients are substances set out in Schedule 1, a homeopathic medicine
or a traditional medicine, that is manufactured, sold or represented for use in
(a) the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal
physical state or its symptoms in humans;
(b) restoring or correcting organic functions in humans; or
(c) Modifying organic functions in humans, such as modifying those functions in a manner
that maintains or promotes health.
4. personal care product (PCP):
For the purposes of this document, defined as a substance or mixture of substances which is
74
generally recognized by the public for use in daily cleansing or grooming. Personal care products
may fall into one of three regulatory categories in Canada: cosmetics, drugs or natural health
products.
5. product at the cosmetic-drug interface (PCDI):
A subset of personal care products, which are not easily distinguished as either a drug or
cosmetic, as defined in the Food and Drugs Act.
The following are the programs within Health Canada that regulate personal care products.
NHPD: Natural Health Products Directorate (Health Products and Food Branch)
PSD: Product Safety Directorate (Healthy Environments and Consumer Safety Branch)
TPD: Therapeutic Products Directorate (Health Products and Food Branch)
Key features of cosmetic regulations
Main features CANADA
Manufacturer has full responsibility for safety of products Yes In market control by authorities
Yes Freedom to use any distribution channel Yes Notification of products Mandatory notification
of product name and function, plus quantitative or semi quantitative ingredients list to be notified
10 days at least after placing the product on the market Quantity labeling Metric labeling mandatory.
Non-metric labeling allowed as a supplement Identity of producer/importer on the labels Name
and address of manufacturer or dealer. Non-Canadian address is accepted.
Please note that test-marketed cosmetics must meet all requirements of the Food and Drugs
Act and the Cosmetic Regulations. There are no exemptions for test-marketing.
The completed Cosmetic Notification Form (CNF) provides specific product information to
Health Canada, including: ü address and contact information of the manufacturer(s), importer(s),
distributor(s), and formulator(s) ü function of the cosmetic ü form of the cosmetic (for example,
cream and gel) ü ingredients of the cosmetic ü concentration of each ingredient.
There is no fee associated with the cosmetic notification process.
The personal information provided to Health Canada is protected under the provisions of
the Privacy Act.
Submission of the CNF does not constitute approval for sale by Health Canada, agreement
that the product is classified as a cosmetic nor that the product complies with all legislative
requirements. Manufacturers and importers are responsible for making sure their cosmetics meet
the requirements of the Food and Drugs Act and its Cosmetic Regulations.
If there are concerns with a submitted notification or product (for example: unknown
ingredients, missing information, safety issues, improper classification, etc.) Health Canada will
inform the responsible company of those concerns. Failure to respond may result in compliance
action.
Examples of cosmetics
❖ soaps
❖ artificial nail builders
❖ adhesives such as for artificial nails, hair extensions, etc.
❖ moisturizers • tinted moisturizers (concealer)
❖ tattoo inks
75
❖ makeup products
❖ tooth whiteners
❖ cleansing wipes
❖ feminine douches
❖ Examples of products that are not considered cosmetic
❖ sunscreens (including makeup products with SPF)
❖ acne treatment
❖ skin whiteners or lighteners
❖ denture cleaners
❖ hand sanitizers
❖ artificial nails and hair extensions
❖ laser treatment hair removers
❖ collagen or “Botox” injections
❖ insect repellents
❖ oral supplements
❖ room or fabric sprays
❖ non-prescription contact lenses
Information on label
❖ This guide covers three aspects of information appearing on the labels of cosmetic products:
❖ the classification of cosmetic products (see section 3).
❖ required declarations that must appear on a label. These include:
❖ product identity (see section 4),
❖ net quantity (see section 5),
❖ name and address of the manufacturer (see definition) (see section 6),
❖ avoidable hazards and cautions (see section 7), and
❖ Ingredients (see section 8).
❖ sources of additional information concerning labelling requirements
Natural health products
Natural health products (NHPs) are naturally occurring substances that are used to restore
or maintain good health. They are often made from plants, but can also be made from animals,
microorganisms and marine sources. They come in a wide variety of forms like tablets, capsules,
tinctures, solutions, creams, ointments and drops.
Natural health products, often called “complementary” or “alternative” medicines, include:
vitamins and minerals, herbal remedies, homeopathic medicines, traditional medicines like
traditional Chinese and Ayurvedic (East Indian) medicines, Probiotics, other products like amino
acids and essential fatty acids
Product authorization
To be licensed in Canada, natural health products must be safe, effective, of high quality
76
and carry detailed label information to let people make safe and informed choices.
You can identify products that have been licensed for sale in Canada by looking for the
eight-digit Natural Product Number (NPN) or Homeopathic Medicine Number (DIN-HM) on the
label.
A NPN or DIN-HM means that the product has been authorized for sale in Canada and is
safe and effective when used according the instructions on the label.
To be legally sold in Canada, all-natural health products must have a product license, and
the Canadian sites that manufacture, package, label and import these products must have site
licenses.
To get product and site licenses, specific labelling and packaging requirements must be met,
good manufacturing practices must be followed, and proper safety and efficacy evidence must be
provided.
Product licensing
All-natural health products must have a product license before they can be sold in Canada.
To get a license, applicants must give detailed information about the product to Health Canada,
including: medicinal ingredients, source, dose, potency, non-medicinal ingredients and
recommended use(s).
Once Health Canada has assessed a product and decided it is safe, effective and of high
quality, it issues a product license along with an eight-digit Natural Product Number (NPN) or
Homeopathic Medicine Number (DIN-HM), which must appear on the label. This number lets
you know that the product has been reviewed and approved by Health Canada.
Labeling
All NHPs must meet specific labelling requirements, to help you make safe and informed
choices about the NHPs you choose to use. Information required on NHP labels includes:
product name, product license number, quantity of product in the bottle, complete list of
medicinal and non-medicinal ingredients, recommended use (including purpose or health claim,
route of administration and dose), any cautionary statements, warnings, contra-indications and
possible adverse reactions associated with the product any special storage condition.

77
dfdff

78
 UNIT - III

CHAPTER 01

Registration of Indian drug product in over-

seas market

Procedure for export of pharmaceutical prod-

ucts

Technical documentation, Drug Master Files

(DMF)

Common Technical Document (CTD)

Electronic Common Technical 163 Document

(eCTD)

ASEAN Common Technical Document

(ACTD)research

76
77
 Registration of Indian drug product in
01
overseas market
Procedure for export of pharmaceutical products
Background
India occupies a third largest position in the world in the field of Pharmaceutical
industry. These industries are regulated by the Ministry of Health & Family Welfare and
Ministry of Chemical & Fertilizers. Despite of its position in Pharmaceutical market and its
growing economy, a well sophisticated Research and Development is not affordable due to
various reasons. To overcome this pitfall, India opens up its pharmaceutical market to MNC’s
and it encourages the trading of the drug in and out of the country. Most of the drugs for the
Indian market are imported from the European Union followed by North America and Asia.
India has a special policy for the purpose of Import and Export called as “EXIM” policy.
This policy gives way to quantitative as well as qualitative improvements in the field of
Research and Development activities.
The Central Drugs Standard Control Organization (CDSCO) regulates the import and
export of the drugs in the country, through 11 Port offices located in different parts of the
country. CDSCO regulates the manufacture, sale, import, export, and clinical research of
drugs in India by the following rules and acts.
1. Drugs and Cosmetics act, 1940 and Rules, 1945.
2. Pharmacy act, 1948
3. Drugs and Magic Remedies act, 1954.
4. Medicinal and Toilet Preparation act, 1956.
5. Narcotic and Psychotropic Substances act, 1985.
6. The Drugs (Prices Control) order, 1995.
The CDSCO also work through state authorities. While, the central authorities are
responsible for approval of new drugs, clinical trials in the country; laying down the
standards for the drugs control over the quality of imported drugs coordination of the state
drug control organizations; the state authorities regulates manufacture, sale and distribution
of drugs, licensing drug testing laboratories, approving drug formulations for manufacture,
carrying out pre and post licensing inspections, for the drugs manufactured and marketed in
the respective states.
The new patent regime has ushered in the era of product patents for the pharmaceutical
sector, in line with the obligations under the World Trade Organization (WTO) and Trade-
Related Aspects of Intellectual Property Rights (TRIPS) Agreement. As a result, the Indian
pharmaceutical industry has become self-reliant in several areas and has developed a sounder
and technologically advanced R&D segment.
The industry offers several opportunities for investments and trade owing to the
following advantageous features:
v Self-reliance displayed by the production of 70% of bulk drugs and almost the entire
requirement of formulations within the country;
v Low cost of production and R & D of quality bulk drugs and formulation s

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v Strong scientific, innovative and technical manpower
v Increasing balance of trade in pharma sector.
v Efficient and cost-effective source for producing generic drugs, especially the drugs
going off patent in the next five years.
v Excellent center for clinical trials in view of the diversity in population.
v Fast growing biotech industry which has great potential in the international market.
Apart from its strength in manufacturing and exporting allopathic medicines, the systems
of medicines like Ayurveda, Unani, Siddha, Yoga, Naturopathy and Homeopathy are also
prevalent in the country.
Rules Related to Export of Drugs from India
A) Rule 94: Packing and labelling of drugs other than Homeopathic
Medicines:
1. Labels on packages or containers of drugs for export shall be adapted to meet the specific
requirements of the law of the Country, to which the drug is to be exported,
Name of the drug
The name, address of the manufacturer and the number of the license under which the drug
has been manufactured
Batch or lot number
Date of expiry
The provisions of Rules 96 to 101 inclusive, shall not apply to a medicine made up ready for
treatment, whether after or without dilution, which is supplied on the prescription of a
registered practitioner provided that:
The medicine is labelled with the following particulars:
The name and address of the supplier;
The name of the patient and the quantity of the medicine;
The number representing serial number of the entry in the prescription register;
The dose, if the medicine is for internal use;
The words -FOR EXTERNEL USE ONLY shall be printed on the label if the medicine is for
external application.
B) Rule 96: Manner of Labeling
The following particulars shall be either printed or written in indelible ink and shall
appear in a conspicuous manner on the label of the innermost container of any drug and on
every other covering in which the container is packed, namely:
a. for drugs included in the Schedule F or Schedule F (1), the name given therein; for
drugs included in the pharmacopoeias and official compendia of drug standards
prescribed in Rule 124, the name or synonym specified in the respective official
pharmacopoeias and official compendia of drug standards followed by the letters I.P.,
or, as the case may be, by the recognized abbreviations of the respective official
pharmacopoeias and official compendia of drug standards;

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b. for drugs included in the National Formulary of India, the name or synonym specified
therein followed by the letters N.F.I.; for other drugs, the international non-proprietary
name, if any, published by the World Health Organization or not Published, the name
descriptive of the true nature or origin of the substance.
Guidelines for the Export of Drug issued by
Ministry of Health and Family Welfare
During the issue of NOC’s for manufacture of new (Unapproved) drug solely for
export, the following conditions shall be taken into consideration:
1. The application shall provide copy of valid export order and NOC will be issued on a
case by case basis against each such order.
2. The applicant shall identify the premises where the drug will be manufactured for
export.
The applicant should mention whether the batch to be exported has undergone Quality
control testing or shall be tested at the destined site.
The applicant shall ensure that the drug(s) manufactured on the basis of NOC given as
per the first condition and it is exported and that no part of it is diverted for domestic sale in
India.
The applicant shall make available for inspection of the appropriate authorities, on
completion of the export orders, information regarding each consignment dispatched,
remaining stock of drug and related raw materials and intermediates in hand.
The applicant shall ensure physical destruction of all un exported quantity of drugs.
This should be included as a condition of manufacturing license issued to the applicant by
the State licensing authority.
The applicant shall ensure that the drug for which NOC has been given shall cease to
be manufactured or exported if the drug is prohibited in future in the country or in the
importing country.
Requirement for Common Submission Format for Issue of
NOC for Export
The following documents are required in the following manner and order for the issue
No Objection Certificate (NOC) for export of drugs from India:
1. Covering letter
Purchase Order: Order from the foreign buyer either in the name of the manufacturer
or trader with the list of products to be exported clearly indicating name of the drug, dosage
form, composition and strength pack size duly signed by the competent authority with specific
destination point of the importing country. It should be signed by the authority with a valid
purchase order no. and recent date not more than 6 months prior to the application made by
the firm.
2. Manufacturing License
Performa Invoice: A copy of Performa invoice from the importing country should
accompany with application for import of unapproved Active Pharmaceutical Ingredients,
used in the drug formulation, it shall be duly signed by the competent authority.

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3. Registration Certificate
Registration certificate required for Common Submission Format for Issue of NOC for
Export

Technical documentation
Background
The agreement to assemble all the Quality, Safety and Efficacy information in a common
format (called CTD - Common Technical Document) has revolutionized the regulatory review
processes, led to harmonized electronic submission that, in turn, enabled implementation of
good review practices. For industries, it has eliminated the need to reformat the information
for submission to the different ICH regulatory authorities.
The CTD is organized into five modules. Module 1 is region specific and Modules 2,
3, 4 and 5 are intended to be common for all regions. In July 2003, the CTD became the
mandatory format for new drug applications in the EU and Japan, and the strongly
recommended format of choice for NDAs submitted to FDA, United States.
Common Technical Document (CTD) for Dossiers
Technical Document (CTD) is a set of specifications for application dossier for the
registration of pharmaceutical products in Europe, Japan and the United States. Common
Technical Documents or CTDs are critical sets of information of a new drug that comprise
the application dossier. The application dossier is then submitted for the purpose of obtaining
approval by regional regulatory authorities before the drug can undergo clinical trials and
subsequently be introduced in the market. These regional regulatory organizations include
the Food and Drug Administration, or the FDA for the United States of America, the European
Medicines Agency, or the EMA for Europe, and the Ministry of Health, Labour, and Welfare
for Japan.
Before these drugs regulatory organizations can receive and review the application
dossiers on the new drugs, the application dossiers need to be prepared in adherence to a
format that is globally agreed upon. The implementation of this standardized format for
CTDs are handled by the International Conference of Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use.
Each CTD is segmented into five modules:
1. Administrative and prescribing information
2. Overview and summary of pharmaceutical drugs
3. Quality (pharmaceutical documentation)
4. Pre-clinical(Pharmacology/Toxicology)
5. Clinical (Efficacy and Safety)
A. Module 1
Each of these modules contain subheadings that are standardized for all jurisdictions
of regulation by the respective regulatory organizations, although the information contained
in the first module, is specific to the federal requirements of each of the organizations, and
contains information pertaining to the application forms and the proposal on the labeling of
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 Figure 1- Module of CTD
the drug in question. Apart from the US, Europe, and Japan, Canada and Switzerland have
also come to adopt the CTD format. Today, the CTD format remains the most preferred
format in the preparation of application dossiers for new drug applications for the FDA,
EMA, and the Ministry of Health, Labour, and Welfare in Japan.
B. Module 2
Module 2 of the CTDs includes summaries containing an overview of the pharmaceutical
drug, and how the drug works. This can refer to the pharmacological category the drug belongs
to, how it can take effect in the body, and what is the recommended clinical use of the drug.
Hence, Module 2 will comprise of information that speaks of the quality of the drug, both
clinically and non-clinically.
Related : Abbreviated New Drug Application (ANDA)
C. Module 3
Module 3 of the CTDs is dedicated to elaborating on the quality control aspects of
developing and testing the drug, namely in the chemistry, manufacturing, and controls of the
formulating the drug. Module 3 of the registration dossier will contain this information in
the same sequence and will be uniformly presented with a table of contents, indicating
subheadings on Drug Substance, and Drug Product. There will also be various other
appendices on specific aspects of the drug, such as the synthesis of the drug substance,
manufacture of the drug product, and container closure.
D. Module 4 and Module 5
Module 4 and Module 5 both contain reports, but of non-clinical and clinical studies
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respectively. The non-clinical study reports in Module 4 are prepared based on the meticulous
evaluation of the proposed drug’s pharmacologic, pharmacokinetic, and toxicological effects,
and are presented and discussed very extensively. Module 5 on the other hand, contains the
raw data of the clinical study reports on the efficacy of the drug in length, with a particular
focus on the benefit-risk aspect of the drug.

Drug Master File

Background
A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA)
that may be used to provide confidential detailed information about facilities, processes, or
articles used in the manufacturing, processing, packaging, and storing of one or more human
drugs. The submission of a DMF is not required by law or FDA regulation. A DMF is
submitted solely at the discretion of the holder. The information contained in the DMF may
be used to support an Investigational New Drug Application (IND), a New Drug Application
(NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application,
or amendments and supplements to any of these.
A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not
approved or disapproved. Technical contents of a DMF are reviewed only in connection
with the review of an IND, NDA, ANDA, or an Export Application.
This guideline does not impose mandatory requirements (21 CFR 10.90(b)). It does,
however, offer guidance on acceptable approaches to meeting regulatory requirements.
Different approaches may be followed, but the applicant is encouraged to discuss significant
variations in advance with FDA reviewers to preclude spending time and effort in preparing
a submission that FDA may later determine to be unacceptable.
Drug Master Files are provided for in 21 CFR 314.420. This guideline is intended to
provide DMF holders with procedures acceptable to the agency for preparing and submitting
a DMF. The guideline discusses types of DMF’s, the information needed in each type, the
format of submissions to a DMF, the administrative procedures governing review of DMF’s,
and the obligations of the DMF holder.
DMF’s are generally created to allow a party other than the holder of the DMF to
reference material without disclosing to that party the contents of the file. When an applicant
references its own material, the applicant should reference the information contained in its
own IND, NDA, or ANDA directly rather than establishing a new DMF.
Definitions
For the purposes of this guideline, the following definitions apply:
1. Agency means the Food and Drug Administration.
2. Agent or representative means any person who is appointed by a DMF holder to serve
as the contact for the holder.
3. Applicant means any person who submits an application or abbreviated application or
an amendment or supplement to them to obtain FDA approval of a new drug or an
antibiotic drug and any other person who owns an approved application (21 CFR 314.3
(b)).

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4. Drug product means a finished dosage form, for example, tablet, capsule, or solution,
that contains a drug substance, generally, but not necessarily, in association with one
or more other ingredients (21 CFR 314.3 (b)).
5. Drug substance means an active ingredient that is intended to furnish pharmacological
activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention
of disease or to affect the structure or any function of the human body, but does not
include intermediates used in the synthesis of such ingredient (21 CFR 314.3 (b)).
6. Export application means an application submitted under section 802 of the Federal
Food, Drug, and Cosmetic Act to export a drug that is not approved for marketing in
the United States.
7. Holder means a person who owns a DMF.
8. Letter of authorization means a written statement by the holder or designated agent or
representative permitting FDA to refer to information in the DMF in support of another
person’s submission.
9. Person includes individual, partnership, corporation, and association. (Section 201(e)
of the Federal Food, Drug, and Cosmetic Act.)
10. Sponsor means a person who takes responsibility for and initiates a clinical investigation.
The sponsor may be an individual or pharmaceutical company, governmental agency,
academic institution, private organization, or other organization (21 CFR 312.3 (b)).
Types of drug master files
There are five types of DMF’s:
Type I- Manufacturing Site, Facilities, Operating Procedures, and Personnel
Type II- Drug Substance, Drug Substance Intermediate, and Material Used in Their
Preparation, or Drug Product
Type III- Packaging Material
Type IV- Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Type V- FDA Accepted Reference Information
1. Type I
Manufacturing Site, Facilities, Operating Procedures, and Personnel
A Type I DMF is recommended for a person outside of the United States to assist FDA
in conducting onsite inspections of their manufacturing facilities. The DMF should describe
the manufacturing site, equipment capabilities, and operational layout. A Type I DMF is
normally not needed to describe domestic facilities, except in special cases, such as when a
person is not registered and not routinely inspected.
The description of the site should include acreage, actual site address, and a map
showing its location with respect to the nearest city. An aerial photograph and a diagram of
the site may be helpful. A diagram of major production and processing areas is helpful for
understanding the operational layout. Major equipment should be described in terms of
capabilities, application, and location. Make and model would not normally be needed unless
the equipment is new or unique. A diagram of major corporate organizational elements, with
key manufacturing, quality control, and quality assurance positions highlighted, at both the
manufacturing site and corporate headquarters, is also helpful.

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2. Type II
Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation,
or Drug Product.
A Type II DMF should, in general, be limited to a single drug intermediate, drug
substance, drug product, or type of material used in their preparation.
Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation
Summarize all significant steps in the manufacturing and controls of the drug intermediate
or substance. Detailed guidance on what should be included in a Type II DMF for drug
substances and intermediates may be found in the following guidelines:
Guideline for Submitting Supporting Documentation in Drug Applications for the
Manufacture of Drug Substances.
Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls
Section of an Application.
Drug Product
Manufacturing procedures and controls for finished dosage forms should ordinarily be
submitted in an IND, NDA, ANDA, or Export Application. If this information cannot be
submitted in an IND, NDA, ANDA, or Export Application, it should be submitted in a DMF.
When a Type II DMF is submitted for a drug product, the applicant/sponsor should follow
the guidance provided in the following guidelines:
Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls
Section of an Application.
Guideline for Submitting Documentation for the Manufacture of and Controls for Drug
Products
Guideline for Submitting Samples and Analytical Data for Methods Validation
3. Type III
Packaging Material: Each packaging material should be identified by the intended use,
components, composition, and controls for its release. The names of the suppliers or
fabricators of the components used in preparing the packaging material and the acceptance
specifications should also be given. Data supporting the acceptability of the packaging
material for its intended use should also be submitted as outlined in the “ Guideline for
Submitting Documentation for Packaging for Human Drugs and Biologics.”
Toxicological data on these materials would be included under this type of DMF, if not
otherwise available by cross reference to another document.
4. Type IV
Excipient, Colorant, Flavor, Essence, or Material Used in their preparation
Each additive should be identified and characterized by its method of manufacture,
release specifications, and testing methods.
Toxicological data on these materials would be included under this type of DMF, if not
otherwise available by cross reference to another document.
Usually, the official compendia and FDA regulations for color additives (21 CFR Parts
70 through 82), direct food additives (21 CFR Parts 170 through 173), indirect food additives
(21 CFR Parts 174 through 178), and food substances (21 CFR Parts 181 through 186) may
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be used as sources for release tests, specifications, and safety. Guidelines suggested for a
Type II DMF may be helpful for preparing a Type IV DMF. The DMF should include any
other supporting information and data that are not available by cross reference to another
document.
5. Types V
FDA Accepted Reference Information
FDA discourages the use of Type V DMF’s for miscellaneous information, duplicate
information, or information that should be included in one of the other types of DMF’s. If
any holder wishes to submit information and supporting data in a DMF that is not covered
by Types I through IV, a holder must first submit a letter of intent to the Drug Master File
Staff (for address, see D.5.a. of this section). FDA will then contact the holder to discuss the
proposed submission.
Each DMF should contain only one type of information and all supporting data. See
Section IV.C of the guideline for more detailed descriptions of the kind of information desired
in each type. Supporting information and data in a DMF can be cross referenced to any other
DMF.
Submissions to drug master files
Each DMF submission should contain a transmittal letter, administrative information
about the submission, and the specific information to be included in the DMF as described
in this section.
The DMF must be in the English language. Whenever a submission contains information
in another language, an accurate certified English translation must also be included.
Each page of each copy of the DMF should be dated and consecutively numbered. An
updated table of contents should be included with each submission.
A. Transmittal Letters
The following should be included:
Original Submissions
a. Identification of submission: Original, the type of DMF as classified in Section III,
and its subject.
b. Identification of the applications, if known, that the DMF is intended to support,
including the name and address of each sponsor, applicant, or holder, and all relevant
document numbers.
c. Signature of the holder or the authorized representative.
d. Typewritten name and title of the signer.
Amendments
a. Identification of submission: Amendment, the DMF number, type of DMF, and the
subject of the amendment.
b. A description of the purpose of submission, e.g., update, revised formula, or revised
process.
c. Signature of the holder or the authorized representative.
d. Typewritten name and title of the signer.
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Administrative Information
Administrative information should include the following:
Original Submissions
a. Names and addresses of the following:
(1) DMF holder.
(2) Corporate headquarters.
(3) Manufacturing/processing facility.
(4) Contact for FDA correspondence.
(5) Agent(s), if any.
c. The specific responsibilities of each person listed in any of the categories in Section a.
c. Statement of commitment.
A signed statement by the holder certifying that the DMF is current and that the DMF holder
will comply with the statements made in it.
Amendments
a. Name of DMF holder.
b. DMF number.
c. Name and address for correspondence.
d. Affected section and/or page numbers of the DMF.
e. The name and address of each person whose IND, NDA, ANDA, DMF, or Export
Application relies on the subject of the amendment for support.
f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on
the subject of the amendment for support, if known.
g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are
affected, if known
Drug Master File Contents
General Information and Suggestions
A. Environmental Assessment
Type II, Type III, and Type IV DMF’s should contain a commitment by the firm that its
facilities will be operated in compliance with applicable environmental laws. If a completed
environmental assessment is needed, see 21 CFR Part 25.
B. Stability
Stability study design, data, interpretation, and other information should be submitted,
when applicable, as outlined in the “Guideline for Submitting Documentation for the Stability
of Human Drugs and Biologics.”
Format, Assembly, and Delivery
-An original and duplicate are to be submitted for all DMF submissions.
Drug Master File holders and their agents/representatives should retain a complete

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reference copy that is identical to, and maintained in the same chronological order as, their
submissions to FDA.
-The original and duplicate copies must be collated, fully assembled, and individually
jacketed.
Each volume of a DMF should, in general, be no more than 2 inches thick. For
multivolume submissions, number each volume. For example, for a 3-volume submission,
the volumes would be numbered 1 of 3, 2 of 3, and 3 of 3.
U.S. standard paper size (8-1/2 by 11 inches) is preferred.
Paper length should not be less than 10 inches nor more than 12 inches. However, it
may occasionally be necessary to use individual pages larger than standard paper size to
present a floor plan, synthesis diagram, batch formula, or manufacturing instructions. Those
pages should be folded and mounted to allow the page to be opened for review without

Figure 2- Format of Drug Master File

disassembling the jacket and refolded without damage when the volume is shelved.
The agency’s system for filing DMF’s provides for assembly on the left side of the
page. The left margin should be at least three fourths of an inch to assure that text is not
obscured in the fastened area. The right margin should be at least one half of an inch. The
submitter should punch holes 8 1/2 inches apart in each page. See the page measurements
shown in the following figure:
Delivery to FDA
Drug Master File submissions and correspondence should be addressed as follows:
Drug Master File Staff
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 Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
Delivery charges to the above address must be prepaid.
Authorization to refer to a Drug Master File
a. Letter of Authorization to FDA
Before FDA can review DMF information in support of an application, the DMF holder
must submit in duplicate to the DMF a letter of authorization permitting FDA to reference
the DMF. If the holder cross references its own DMF, the holder should supply in a letter of
authorization the information designated by items 3, 5, 6, 7, and 8 of this section. The holder
does not need to send a transmittal letter with its letter of authorization.
The letter of authorization should include the following:
1. The date.
2. Name of DMF holder.
3. DMF number.
4. Name of person(s) authorized to incorporate information in the DMF by reference.
5. Specific product(s) covered by the DMF.
6. Submission date(s) of 5, above.
7. Section numbers and/or page numbers to be referenced.
8. Statement of commitment that the DMF is current and that the DMF holder will comply
with the statements made in it.
9. Signature of authorizing official.
10. Typed name and title of official authorizing reference to the DMF.
b. Copy to Applicant, Sponsor, or Other Holder
The holder should also send a copy of the letter of authorization to the affected applicant,
sponsor, or other holder who is authorized to incorporate by reference the specific information
contained in the DMF. The applicant, sponsor, or other holder referencing a DMF is required
to include a copy of the DMF holder’s letter of authorization in the application.
Processing and Reviewing Policies
a. Policies Related to Processing Drug Master Files
Public availability of the information and data in a DMF is determined under 21 CFR
Part 20, 21 CFR 314.420(e), and 21 CFR 314.430.
An original DMF submission will be examined on receipt to determine whether it meets
minimum requirements for format and content. If the submission is administratively
acceptable, FDA will acknowledge its receipt and assign it a DMF number.
If the submission is administratively incomplete or inadequate, it will be returned to
the submitter with a letter of explanation from the Drug Master File Staff, and it will not be
assigned a DMF number.

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b. Drug Master File Review
A DMF is never approved Or disapproved. The agency will review information in a
DMF only when an IND sponsor, an applicant for an NDA, ANDA, or Export Application,
or another DMF holder incorporates material in the DMF by reference. As noted, the
incorporation by reference must be accompanied by a copy of the DMF holder’s letter of
authorization.
If FDA reviewers find deficiencies in the information provided in a DMF, a letter
describing the deficiencies is sent to the DMF holder. At the same time, FDA will notify the
person who relies on the information in the deficient DMF that additional information is
needed in the supporting DMF. The general subject of the deficiency is identified, but details
of the deficiency are disclosed only to the DMF holder. When the holder submits the requested
information to the DMF in response to the agency’s deficiency letter, the holder should also
send a copy of the accompanying transmittal letter to the affected persons relying on the
DMF and to the FDA reviewing division that identified the deficiencies. The transmittal
letter will provide notice that the deficiencies have been addressed.
Holder obligations
Any change or addition, including a change in authorization related to specific
customers, should be submitted in duplicate and adequately cross referenced to previous
submission(s). The reference should include the date(s), volume(s), section(s), and/or page
number(s) affected.
Notice Required for Changes to a Drug Master File
A holder must notify each affected applicant or sponsor who has referenced its DMF of
any pertinent change in the DMF (21 CFR 314. 420(c)). Notice should be provided well
before making the change in order to permit the sponsor/applicant to supplement or amend
any affected application(s) as needed.
Listing of Persons Authorized to Refer to a Drug Master File
A DMF is required to contain a complete list of persons authorized to incorporate
information in the DMF by reference [21 CFR 314.420(d)]. The holder should update the
list in the annual update. The updated list should contain the holder’s name, DMF number,
and the date of the update. The update should identify by name (or code) the information
that each person is authorized to incorporate and give the location of that information by
date, volume, and page number.
Any person whose authorization has been withdrawn during the previous year should
be identified under a suitable caption.
If the list is unchanged on the anniversary date, the DMF holder should also submit a
statement that the list is current.
Annual Update
The holder should provide an annual report on the anniversary date of the original
submission. This report should contain the required list as described in B.1., and should
also identify all changes and additional information incorporated into the DMF since the
previous annual report on the subject matter of the DMF. If the subject matter of the DMF is
unchanged, the DMF holder should provide a statement that the subject matter of the DMF
is current.

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 Failure to update or to assure FDA annually that previously submitted material and
lists in the DMF remain current can cause delays in FDA review of a pending IND, NDA,
ANDA, Export Application, or any amendment or supplement to such application; and FDA
can initiate procedures for closure of the DMF (see Section IX).
Appointment of an Agent
When an agent is appointed, the holder should submit a signed letter of appointment to
the DMF giving the agent’s name, address, and scope of responsibility (administrative and/
or scientific). Domestic DMF holders do not need to appoint an agent or representative,
although foreign DMF holders are encouraged to engage a U.S. agent.
Transfer of Ownership
To transfer ownership of a DMF to another party, the holder should so notify FDA and
authorized persons in writing. The letter should include the following:
v Name of transferee
v Address of transferee
v Name of responsible official of transferee
v Effective date of transfer
v Signature of the transferring official
v Typewritten name and title of the transferring official.
The new holder should submit a letter of acceptance of the transfer and an update of
the information contained in the DMF, where appropriate. Any change relating to the new
ownership (e.g., plant location and methods) should be included.
Major reorganization of a drug master file
A holder who plans a major reorganization of a DMF is encouraged to submit a detailed
plan of the proposed changes and request its review by the Drug Master File Staff. The staff
should be given sufficient time to comment and provide suggestions before a major
reorganization is undertaken.
Closure of a drug master file
A holder who wishes to close a DMF should submit a request to the Drug Master File
Staff stating the reason for the closure. See Section IV.D.5.a for the address.
The request should include a statement that the holder’s obligations as detailed in
Section VII have been fulfilled.
The Agency may close a DMF that does not contain an annual update of persons
authorized to incorporate information in the DMF by reference and a list of changes made
since the previous annual report. The holder will be notified of FDA’s intent to close the
DMF.

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 Electronic Common Technical 163 Document (eCTD)
Background
eCTD (electronic Common Technical Document) is a standard format of submitting
Regulatory information (such as applications, supplements, and reports) to the concerned
Health Authorities (HAs). It provides a harmonized solution to implement the Common
Technical Document (CTD) electronically. An eCTD consists of individual documents in
PDF format which are arranged in a hierarchical form as per the CTD structure. It also has
an XML backbone which cross-links required documents and provides information regarding
the submission. The purpose of introducing eCTD was to reduce the burden on the reviewers
of the HAs. It also simplifies the process of submission as all the Regulatory authorities use
it as a standard format.
There are total five modules in eCTD
1. Region-specific information
2. Summary documents
3. Information related to quality
4. Non-clinical study reports
5. Clinical study reports (CSRs)
eCTD submissions are accepted for the following applications
v Investigational New Drug (INDs)
v New Drug Applications (NDAs)
v Abbreviated New Drug Applications (ANDAs)
v Biologics License Applications (BLAs)
v All the applications following the submission of the above-stated applications
v All the Master Files (MFs) which are part of any above-mentioned applications
v Major countries, such as the US, Europe, Australia, Canada, South Africa, Thailand,
and Japan, are using eCTD as a standard format for submissions of documents because
of numerous advantages that it offers over the traditional submission method. Some of
which are:
v Allows agencies to upload sequences automatically with the help of XML backbone
v Reviewers can refer information easily with the help of hyperlinks
v No need to scan, copy or store paper documents
v Changes and updates made to the dossiers can be easily identified
v Easy product lifecycle tracking
v Simultaneous accessibility of documents is possible
v eCTD is already included in global submission strategies of companies, worldwide. To
stay ahead in the competition, companies are required to stay up-to-date with the eCTD
r eq u i re m e n t s . A r e yo u r s u b m i s s i o n s e C TD c o m p l i a n t ? R e ac h t o F re yr
at sales@freyrsolutions.com to know more about eCTD submissions.

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 The Asian common technical dossier (actd) for the registration
of pharmaceuticals for humanuse
Organization of the dossier
This ASEAN Common Technical Dossier (ACTD) is a guideline of the agreed upon
common format for the preparation of a well-structured Common Technical Dossier (CTD)
application that will be submitted to ASEAN regulatory authorities for the registration of
pharmaceuticals and biologics for human use. Although the current ASEAN Common
Technical Requirements (ACTR) has not included specific requirements for bio-similar
products, the ACTD format is also applicable for bio-similar products. This guideline
describes a CTD format that will significantly reduce the time and resources needed to compile
applications for registration and in the future, will ease the preparation of electronic
documental submissions. Regulatory reviews and communication with the applicant will be
facilitated by a standard document of common elements.
This guideline merely demon stratesan appropriate write-up format foracquireddata.
However, applicants can modify, if needed, to provide the best possible presentation of the
technical information, in order to facilitate the understanding and evaluation of the results
upon pharmaceutical registration.
Throughout the ACTD, the display of information should be unambiguous and
transparent, in order to facilitate the review of the basic data and to help a reviewer become
quickly oriented to the application contents. Text and tables should be prepared using
margins that allow the document to be printed on either A4 or 8.5” x 11” paper. The left-hand
margin should be sufficiently large that information is not obscured by the method of binding.
Font and size, (Times New Roman, 12-point font), for text and tables should be of a
style and size that are large enough to be easily legible, even after photocopying. Every page
should be numbered, with the first page of each part designated as page 1. For a paper,
Common Technical Acronyms and abbreviations should be defined the first time they are
used in each part. References should be cited in accordance with the 1979 Vancouver
Declaration on Uniform requirements for Manuscripts Submitted to Biomedical Journals.
The Common Technical Document is organized into four parts asfollows:
Part I
Table of Contents, Administrative Data and Product Information
Part I contains initially the overall Table of Contents of the whole ACTD to provide
basically the information that could be looked through respectively. Secondly, the next content
is the Administrative Data where required specific documentation in detail is put together
such as application forms, label, and package insert etc. The last section of this part is Product
Information where necessary information includes prescribed information, mode of action,
side effects etc. A general introduction to the pharmaceutical, including its pharmacologic
class and mode of action should be included. Part II. Quality Document
Part I contain Table of Content Administrative Information and Prescribing Information
Section A: Introduction
Section B: Overall ASEAN Common Technical Dossier Table of Contents
Section C: Documents required for registration (for example, application forms,

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labelling, Product Data Sheet, prescribing information)
Part II
Quality Document
It should provide the Quality Overall Summary followed by the Body of Data. The
quality control document should be described in detail as much as possible.
Part II contain three sections
Section A: Table of Contents
Section B: Quality Overall Summary
Section C: Body of Data
Part III
Non-clinical Document
Part III should provide the Nonclinical Overview, followed by the Nonclinical Written
Summaries and the Nonclinical Tabulated Summaries. The documentation of this part is not
required for Generic Products, Minor Variation Products and some Major Variation Products.
For ASEAN member countries, the Study Reports of this part may not be required for NCE,
Biological Products and other Major Variation Products if the Original Products are already
registered and approved for market authorization in Reference Countries. Therefore, the
authority who requires specific Study Reports should ask for the necessary documents.
The word “Nonclinical” replaces “Pre-clinical”.
Part III contain four sections
Section A: Table of Contents
Section B: Nonclinical Overview
Section C: Nonclinical Written and Tabulated Summaries
1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology
Section D: Nonclinical Study Reports
1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology
Part IV
Clinical Document
Part IV should provide the Clinical Overview and the Clinical Summary. The
documentation of this part is not required for Generic Products, Minor Variation Products
and some Major Variation Products. For ASEAN member countries, the Study Reports of
this part may not be required for NCE, Biological Products and other Major Variation Products
if the Original Products are already registered and approved for market authorization in

94
Reference Countries. Therefore, the authority who requires specific Study Reports should
ask for the necessary documents.
The overall organisation of the Common Technical Dossier is presented on the following
in Parts:
Section A: Table of Contents
Section B: Clinical Overview
Section C: Clinical Summary
1. Summary of Bio-pharmaceutics and Associated Analytical Methods
2. Summary of Clinical Pharmacology Studies
3. Summary of Clinical Efficacy
4. Summary of Clinical Safety
5. Synopses of Individual Studies
Section D: Tabular Listing of All Clinical Studies
Section E: Clinical Study Reports
Section F: List of Key Literature Reference

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 UNIT - IV

CHAPTER 01

Clinical trials

Developing clinical trial protocols

Institutional Review Board / Independent

Ethics committee –

formation and working procedures

Informed consent process and procedures

GCP obligations of Investigators

sponsors & Monitors

Managing and Monitoring clinical trials

Pharmacovigilance - safety monitoring in

clinical trials

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dfdf

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 Clinical trials
01

Background
Clinical trials developing clinical trial protocols
Writing a research proposal is probably one of the most challenging and difficult tasks
as research are a new area for the majority of postgraduate sand new researchers. The purpose
of this article is to summarize the most important steps and necessary guidelines for producing
a standard research protocol. Academic and administrative success of any project is usually
determined by acquiring a grant for the related field of research. Hence, the quality of a
protocol is primarily required to achieve success in this scientific competition.
Clinical research is conducted according to a plan (a protocol) or an action plan. The
protocol demonstrates the guidelines for conducting the trial. It illustrates what will be made
in the study by explaining each essential part of it and how it is carried out. It also describes
the eligibility of the participants, the length of the study, the medications and the related
tests.
A protocol is directed by a chief researcher. The health of the participants’ will be
regularly checked by members of the research team to ultimately ensure the study’s safety
and effectiveness.
Purpose of a Research Proposal
1. To raise the question to be researched and clarify its importance.
2. To collect existing knowledge and discuss the efforts of other researchers who have
worked on the related questions (Literature view).
3. To formulate a hypothesis and objectives.
4. To clarify ethical considerations.
5. Tosuggest the methodology required forsolving the question and achieving the
objectives.
To discuss the requirements and limitations in achieving the objectives.
Benefits of the Proposal to a Researcher
Allows the researcher to plan and review the project’s steps. Serves as a guide
throughout the research.
Forces time and budget estimates.
Writing the protocol
Protocol writing allows the researcher to review and critically evaluate the published
literature on the interested topic, plan and review the project steps and serves as a guide
throughout the investigation. The proposal is an inevitable document that enables the
researcher to monitor the progress of the project.
1. Title of the study
2. Administrative details
3. Project summary

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4. Introduction to the research topic, background (Literature view)
6. Study objectives and/or questions. Statement of the problem.
7. Methodology: Study design, study population and methods of recruitment, variables
list, sample size, methods of data collection, data collection tools, plan of analysis
(analysis of data)
8. Project management: Work plan (Timeline-proposed schedule)
9. Strengths and limitations of the study
10. Issues for ethical review and approvals
Title of the study
Title of proposal should be accurate, short, concise, and identify. What is the study
about, Who are the targets, Where is the setting of the study and when it is launched, if
applicable. It should make the main objective clear, convey the main purpose of the research
and mention the target population. Carry maximum information about the topic in a few
words; it is a good practice to keep the title to within12-15words. It should convey the idea
about the area of research and what methods are going to be used in a compact, relevant,
accurate, attractive, easy to understand, and informative way.
Administrative Details
The following administrative details and a protocol content summary should follow
the title page:
a. Contents page list of relevant sections and sub-sections with corresponding page
number.
b. Signature page is signed by senior members of the research team and dated to
confirm that the version concerned has been approved by them.
c. Contact details for the research team members listing postal and e-mail addresses
and telephone numbers for members of the research team.
Project summary
The summary should be distinctive, concise and should sum up all the essentials of the
protocol.
Introduction (Background)
The background to the project should be concise and refer to the subject straight
forwardly. In writing there view, attention should be drawn to the positives, negatives and
limitations of the studies quoted. Introduction is concluded by explaining how the present
study will benefit the community. The literature view should logically lead to the statement
of the aims of the proposed project and end with the aims and objectives of the study. There
view should include the most recent publications in the field and the topic of the research is
selected only after completing the literature review and finding some gaps in it.
Introduction should briefly answer the importance of the topic, the gaps/lacunae in the
literature, the purpose of the study and benefits for the society, from the study.
The research question should be described precisely and concisely. It is going to be the
basis of designing the project. The definition of the problem should be clear so that areadercan
straight forwardly recognize the real meaning of it.

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Study objectives (Aims)
The aims should be explicitly stated. These should be confined to the intention of the
project and they should arise from the literature review. State the goal you need to achieve.
The study aims or objectives emerge from the study questions/ hypothesis. They are answers
to what are the possible responses to the research question or hypothesis under analysis and
measure. Aims should be logical and coherent, feasible, concise, realistic, considering local
conditions, phrased to clearly meet the purpose of the study and related to what the specific
research is intended to accomplish. For example, to evaluate knowledge level regarding
dental caries in primary school children in KSA (this is not detailed). The following should
be added: Causes, treatment, preventive measures, etc.
The objectives should be (SMART objective): Specific, Measurable, Achievable,
Relevant and Time based.
a. Specific Aims: Details of each objective that will finally lead to the achievement of
the goal should be stated. Specific aims one by one should be listed concisely. It is good
practice not to include too many aims in the study (2-5 best); too many objectives often lead
to in accurate and poorly defined results. Furthermore, aims should be achievable, realistic
and specific with no general and ambiguous statements. They should be stated inaction verbs
that illustrate their purpose: i.e., “to determine, to compare, to verify, to calculate, to reduce,
to describe, etc.
b. Secondary objectives (optional): These are referred to as ancillary and minor objectives
that could be studied during the course of the study the formulation of objectives helps to
focus the study and to avoid the collection of any unnecessary data and hence organize the
study in clear and distinct stages.
c. Hypothesis: It is a statement based on sound scientific theory that recognizes the
predicted or relation between two or additional assessable variables [11]. It is always
developed in response to the purpose statement or to answer the research questions posed.
Furthermore, hypothesis transforms research questions into a format amendable to testing
or into a statement that predicts an expected outcome.
Types of hypothesis statements:
Null hypothesis:
A null hypothesis is a statement that there is no actual relationship between variables
(H0 or HN). It may be read as there is no difference between the groups to be compared and
no relationship between the exposure and outcome under investigation. H0 states the
contradictory of what the researchers expect. The final conclusion of the investigators will
either keep a null hypothesis or reject it in support of an alternative hypothesis. It does not
essentially mean that H0 is accurate when not rejecting it as there might not be an adequate
proof against it.
Alternative hypothesis
An alternative hypothesis isa statement that suggests a potential outcome that the
researcher may expect (H1 or HA). This hypothesis is derived from previous studies where
an evident difference between the groups to be compared is present. It is recognized only
when a null hypothesis is rejected. Practically, hypotheses are state din the null form, because
they have their inferential statistics. Such hypotheses of no difference will be challenged by
researchers and the result of the statistical testing gives the probability that the hypothesis
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of no difference is true or false.
Aims should be logically linked and arranged according to the tested hypothesis
statement.
Example:
Research question: Is there a difference in fluoride release between the Compomer and
Glass- ionomer cement?
Null Hypothesis: There is no difference in fluoridere lease between the Compomer and
Glass- ionomer cement.
Alternate Hypothesis: There is a difference in fluoride release between the Compomer
and Glass-ionomer cement.
v The statement of the problem should provide a summary of exactly what the project is
trying to achieve.
v What exactly do you want to study?
v Why is it worth studying?
v Does the proposed study have theoretical and or practical significance?
v Does it contribute to a new understanding of a phenomenon? (i.e., Does it address new
or little-known material or does it treat familiar material in a new way or does it
challenge an existing understanding or extend existing knowledge?)
v The justification of the research should be a convincing statement for the need to do it:
v How does the research relate to the priorities of the region and the country?
v What knowledge and information will be obtained?
v What is the ultimate purpose that the knowledge obtained from the study will serve?
v How will the results be disseminated? How will the results be used, and who will be
the beneficiaries?
Methodology
Methods and Materials
It should describe in detail the ‘Where’, ‘Who’, ‘How’ the research will be conducted.
It explains the study design and procedures and techniques used to achieve the proposed
objectives. It defines the variables and demonstrates in detail how the variables will be
measured. It details the proposed methodology for data gathering and processing.
Methodology composes an important part of the protocol. It assures that the hypothesis
will be confirmed or rejected. It also refers to a thorough strategy to attain the objectives.
The methods and materials are divided in to various subheadings:
a. Study design (cross-sectional, case-control, intervention study, Rct, etc.)
Proper explanation should be given as to why a particular design was chosen (on the
basis of proposed objectives and availability of resources).
A study design is in fact the researcher’s general plan to acquire the answer(s) to the
hypothesis being tested. Here, strategies will be applied to develop balanced, correct,
objective and meaningful information. It explains the methods that will be used to collect
and analyze data. Proper selection of the study design is important to attain reliable and
valid scientific results. Ethics, logistic concerns, economic feature sand scientific
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thoroughness will determine the design of the study. Here, a chief concern is given to the
legality of the results including potential bias mystifying issues. Randomized controlled
clinical trial is the best to document a causal relationship between an exposure and its outcome
[Table/Fig-4].
Purpose study Design
l Cross-sectional
To determine frequency and burden of a disease survey (Prevalence)
l Cohort study (Incidence)
l Cohort study
To identify the risk factors l Case-Control study
To determine prognosis of a disease l Cohort study
To determine efficacy/effectiveness of a new treatment l Clinical trials
l Community intervention
To evaluate community programs l Evaluation
b. Study population (Study subjects)
Where are you going to do the research and who is the study population (why doing
research in this place and why selecting this population?).
It describes in detail about the study subjects, all aspects of the selection procedure
and sample size calculation. Proper definition of eligibility, inclusion, exclusion and
discontinuation criteria of the study subjects should be stated. Allocation of subjects to study
arms should be explained and described in details bearing in mind the concealment and
randomization process.
c. Sample size
Sample size calculation is recommended for economical and ethical reasons [16-18].
The calculation of the sample size must be explained including the power of the sample.
The sampling technique should be mentioned, e.g., randomization that will be used in order
to obtain a representative sample for your target population. Each step involved in the
recruitment of the study subjects should be described according to the selection criteria
(inclusion and exclusion criteria). “Informed consent” should be mentioned (Permission
granted in full knowledge of the possible consequences).
d. Proposed intervention
Full description of proposed intervention should be given. Here, all the activities and
actions should be recorded and thoroughly explained in their order of occurrence. When
using drugs, both scientific and brand name should be mentioned followed by the name of
the manufacturi ng company, city, and country. Drug rout e, dosage, frequency of
administration, and total duration of treatment with the drug should be mentioned. When
using apparatus its name should be given followed by the name of the manufacturer, city
and country.
Involved personnel should precisely define:
v Who will be responsible for the interventions?

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v What activities each personnel will perform and with what frequency and intensity?
e. Data collection methods, instruments used:
Data collection tools are:
v Retrospective data (medical records)
v Questionnaires
v Interviews (Structured, Semi-Structured)
v Laboratory test (literature or personal knowledge should be referenced, if established
test, or description should be provided in details, if not established)
v Clinical examinations
v Description of instruments, tools used for data collection, as well as the methods used
to test the validity and reliability of the instrument should be provided.
f. Data Managements and Analysis Plan
This section should be written following statistical advice from a statistician. The
analysis plan and which statistical tests will be used to check the significance to the research
question/hypothesis with appropriate references should be described. Names of variables
that will be used in the analyses and the name of statistical analysis that will be performed
to assess the outcome should be listed.
If computer programs are to be applied, it is important to mention the software used
and its version.
Project Management
Work plan-A work plan is an outline of activities of all the phase of the research to be
carried out according to an anticipated time schedule. Proper time table for accomplishing
each major step of the study should be defined. Assigning time frame to each step in the trial
will be helpful in organizing the structure of the research trial. The personnel (investigators,
assistants, laboratory technicians etc.) involved in the study or data collection should be
properly trained.
1. Strengths and limitations:
It is important to mention the strengths or limitations of the study, i.e., what study can
achieve or cannot achieve is important, so as to prevent wasteful allocation of resources.
2. ethical considerations (issues for ethical Review and Approvals)
It should indicate whether the procedures to be followed are in accord with the
Declaration of Helsinki. In any case, study should not start unless approval from ethics
committee is received.
The following points should be explained:
- The benefits and risks for the subjects involved. The physical, social and psychological
implications of the research.
- Details of the information to be given to the study patients including alternative
treatments/approaches.
- Information should be provided on the free informed consent of the participants.
Information form should contain: Justification for research, outline of study, risks,
confidentiality, and voluntary participation should be told patients about the freedom
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 to withdraw from the study whenever they wish to. Confidentiality indicates show the
personal information obtained from the patient will be kept secret (Data safety).
3. Operational Planning and Budgeting (Budget summary)
Outline the budget requirement showing head wise expenditure for the study-man power,
transportation, instruments, laboratory tests and cost of the drug. Budget estimate is to be
attached in the annexure. All costs including personnel, consumables, equipment, supplies,
communication and funds for patients and data processing are all included in the budget.
Each item should be justified

Institutional Review Board / Independent Ethics committee

(IRB/IEC)
Formation and working procedures
Institutional Review Board/Independent Ethics Committee (IRB/IEC) • IRB/IEC serves
as an independent body that reviews, evaluates, approves and decides on the scientific and
ethical aspects of the clinical trial protocol as well as the benefits and risks to the study
participants • Main purpose of IRB/IEC is to protect the rights, safety, and well-being of the
subjects who participate in a trial
Composition of IRB/IEC
v Consists of members, who collectively have the qualifications and experience to review
and evaluate the science, medical aspects, and ethics of the proposed trials
v Includes at least five members, of which at least one member whose primary area of
interest is nonscientific, and at least one member who is independent of the institution/
trial site
Responsibilities of IRB/IEC
v Safeguard the rights, safety, and well-being of all trial subjects
v Reviews a proposed clinical trial within a reasonable time and document its views in
writing
v Conducts continuing review of each ongoing trial at least once per year
v Ensures that information regarding payment to subjects (including the methods,
amounts, schedule of payment) is set forth in the written informed consent form and
any other written information is provided to the subjects
Procedures of IRB/IEC
v Determines its composition and authority under which it is established
v Schedules, notifies its members of, and conducts its meetings
v Conducts initial and continuing review of trials
v Specifies that no subject should be admitted to a trial before the IRB/IEC issues its
written approval/favorable opinion of the trial
v Specifies the information that the investigator should promptly report to the IRB/IEC
(like deviations from the protocol, adverse drug reactions etc.)

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Maintenance of records of IRB/IEC
v IRB/IEC retains all relevant records (e.g., written procedures, lists of occupations/
affiliations of members, submitted documents, minutes of meetings, etc.) for a period
of at least 3 years after completion of the trial and makes them available upon request
from the regulatory authority(is)
v IRB/IEC may be asked by investigators, sponsors, or regulatory authorities to provide
copies of its written procedures and membership lists

Informed consent process and procedures

Introduction
Informed consent - the process of communication between a patient or research subject
and a physician or researcher that results in the explicit agreement to undergo a specific
medical intervention - is an ethical concept based on the principle that all patients and research
subjects should understand and agree to the potential consequences of the clinical care they
receive. Regulations that govern the attainment of informed consent for treatment and research
are crucial to ensuring that medical care and research are conducted in an ethical manner
and with the utmost respect for individual preferences and dignity. These regulations,
however, often require - or are perceived to require - that informed consent documents and
related materials contain language that is beyond the comprehension level of most patients
and study participants
The Informed Consent Process
The informed consent process is central to the ethical conduct of research. It is an
ongoing conversation between the human research subject and the researchers that begins
before consent is given and continues until the end of the subject’s involvement in the research
(see consent process diagram, below). There are various tools for the investigator to use to
optimize this conversation, but the most important feature of informed consent is the
investigator commitment to the process.
Goals of the informed consent process
v Give the subject information about the research
v Make sure the subject has time to consider all options
v Answer all of the subject’s questions before the decision is made
v Make sure that all information is understood by the subject
v Obtain the subject’s voluntary informed consent to participate
v Continue to inform the subject throughout the research study
v Continue to re-affirm subject consent to participate throughout the research study
Tools an investigator might use to assist the informed consent process
v Consent Form - also called Informed Consent Form (ICF), Informed Consent Document
(ICD) or Patient Consent Form(PCF)*
v Pamphlets or other reading materials*
v Internet information*

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v Instruction sheets*
v Audio-visual presentations*
v Charts or diagrams*
v Discussions
v Consultation with others
*These items require IRB review before use.
Investigator responsibilities in regard to informed consent
v Obtain consent before initiating study-specific procedures.
v Provide a quiet, comfortable, and private setting for the informed consent process
whenever possible.
v Explain the consent process to the subject.
v Make sure the subject has time to consider all options; allow subject to take the form
home before signing (whenever possible).
v Consider the subject’s reading abilities. Check to make sure WIRB has not disallowed
subjects unable to read. If enrollment of limited or non-readers is allowed, involve an
impartial witness in the informed consent process.
v Answer all questions.
v To the extent possible, make sure the subject understands enough information about
the research study to give informed consent.
v To the extent possible, make sure the subject can consent free from coercion or other
undue influence.
v Since the informed consent process continues throughout the subject’s participation in
the study, consent should be informally verified on a continuing basis.
v Significant new information must be given to the subject, and continuing consent
documented in some way; for example, new risk information presented to the subjected
in an addendum to be signed by subjects who agree to continue to participate.
Issues to consider during the consent process
v Was the subject alert and, in your opinion, able to read and understand the language in
the consent form?
v If the subject was unable to read the consent form, and limited or non-readers were
allowed to participate, did you have an impartial witness present for the entire process?
(An impartial witness is someone with adequate reading ability who is independent of
the trial, who cannot be unfairly influenced by people involved in the trial, who attends
the informed consent process while the consent form is being read to the subject, who
reads the informed consent form and any other written information supplied to the
subject, and who is willing to attest to this by signing the consent form).
v If the subject is not fluent in English, was an approved translation of the consent form
provided in the primary language of the subject? Was there also a bilingual translator
present to assist with the informed consent process? Note: a translator alone is not
considered adequate.
v Was the subject under any pressure (for example, family pressure, lack of medical
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 insurance) to participate in the research? Was this discussed?
v Did the subject take time to carefully read the consent form, or read it along with you?
v Were the risks as set forth in the consent form carefully explained to the subject?
v Are there any other risks or concerns not stated in the consent form and were these
explained to the subject?
v Was the subject asked if he or she had any questions about the study?
v Did the subject have any questions or concerns?
v Were the subject’s questions answered?
v Was the subject satisfied with the answer(s) they were provided?
v Did the person conducting the consent discussion check for subject understanding by
asking some basic questions about the research? Did the responses reflect adequate
understanding?
v Did the subject express a clear decision to proceed with the study?
v Was the consent form signed by the person who conducted the informed consent
discussion?
v Was the consent form signed by a witness (if required)?
v Was the consent form signed by the Principal Investigator (if required)?
v If a Legally Authorized Representative is allowed to sign for the subject
v subject’s understanding and assent considered and addressed?
Consent by Legally Authorized Representatives
The laws regulating who can consent for adults who lack the capacity to consent for
themselves are defined at the state level and vary from state to state. Persons who can consent
for adults who lack the capacity to personally provide informed consent are known as Legally
Authorized Representatives (LARs). See 45 CFR 46.102(c) and 21 CFR 50.3(l). Such trials,
unless an exception is justified, should be conducted in individuals having a disease or
condition for which the investigational product is intended.
WIRB’s initial review submission forms solicit information about plans for use of LARs
from investigators who plan to enroll adults who lack the capacity to consent for themselves.
Sites should be able to explain how they determine which individuals meet.
the criteria for being a Legally Authorized Representative (LAR) under their state/
provincial and local law. WIRB can provide a copy of the relevant statutes for your state
upon request; however, advice from your legal counsel is strongly recommended. Sites should
also be able to explain the process they use for verifying that an individual is qualified to
serve as an LAR.
If the site’s state/provincial/local laws regarding Legally Authorized Representatives
are difficult to interpret, the sites may provide the Board with a letter from legal counsel
which includes a statement such as the following: “The individuals who are authorized under
state law to consent on behalf of a prospective subject to that subject’s participation in the
procedures involved in this research protocol are
Consent by Subjects Who Cannot Physically Sign the Consent Form (due to physical
impairment)

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 WIRB does not require a Legally Authorized Representative to provide consent for
subjects who are cognitively capable of consenting, but physically unable (for example, due
to paralysis). In those cases, obtaining consent from the subject with the assistance of a
witness is usually sufficient. WIRB can provide additional guidance for these situations
uponrequest.
Waivers of Consent for non-FDA studies
If you are requesting a waiver of consent and the research is not an FDA regulated
study, then criteria from 45 CFR 46.116(d) must be met:
v The research involves no more than minimal risk to the subjects.
v The waiver or alteration will not adversely affect the rights and welfare of the subjects.
v The research could not practicably be carried out without the waiver or alteration.
v Whenever appropriate, the subjects will be provided with additional pertinent
information after participation.
Waivers of Consent for FDA studies
For FDA regulated studies, waiver of consent must meet requirements of either 21
CFR (a) - (c) (waiver of consent for individual emergency use) or 21 CFR 50.24 (emergency
research without consent), or FDA guidance issued 04-25-2006 for In Vitro Diagnostic Device
Study Using Leftover Human Specimens That Are Not Individually Identifiable.
For individual emergency waivers of consent, prospective IRB approval is not always
necessary if a patient’s life can be saved. See the FAQ on www.wirb.com titled “What is the
difference between “Emergency Use” and “Treatment Use,” and how do I determine which
situation I have?” for more information, or refer to 21 CFR 50.23 (a)-(c).
Waiver of Documentation of Consent
A waiver of documentation of consent is a waiver of the requirement for a signature on
a consent form. The regulations allow the Board to approve this type of waiver if:
v The research is of minimal risk and involves no procedures for which written consent
is usually required; or
v The only record linking the subject and the research would be the consent document
and the principal risk of the research is the risk of breach of confidentiality.
Subjects enrolling in a study under this type of waiver must be provided with the
elements of consent required by the regulations and subjects must consent to participate.
The Board will need to review the information that is provided to subjects to obtain
consent to ensure that the required elements of consent are included in the consent discussion.
Investigators requesting a waiver of documentation of consent must submit a written statement
or script of this information for the Board’s review.
The Consent Form
The primary informed consent tool that involves both the researcher and the IRB is the
consent form. This document is used in all research for which there is no approved waiver of
consent. Thus, most research will involve use of an IRB-approved consent form.
An approved consent form must comply with several regulatory requirements:
v The required elements (as defined by the regulations) must be appropriately included.

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v The content of the consent form must be understandable to anon-scientist.
v No waiver of rights or other exculpatory wording may be present or appear to be present
in the consent form.
Satisfying the above requirements presents a joint challenge to the IRB and the
investigator. In order to obtain WIRB approval of a consent form, the investigator may opt
to do one, or a combination, of the following:
v Submit a sponsor template consent form for review (for multi-center studies, the sponsor
template has often already been submitted to WIRB and reviewed)
v Submit an investigator-written consent form for review
v Request WIRB write the consent form
Some general guidelines for writing consent form
Consent templates and/or outlines are available from WIRB, as well as from some NIH
groups such as NCI, and other sources. See Appendix 1 for a sample Consent Template.
Consent templates provide a framework and structure upon which to build a consent form.
v Consent forms should be written in simple, non-technical language for readers of a
seventh-grade reading level who may not have taken science courses in school.
v Use the term “subject” rather than “patient” (the term “participant” may be used in
some behavioral research).
v Avoid statements that suggest any waiver of subject rights or release from liability of
the investigator or sponsor.
v Avoid use of “I understand” or “you understand” language as this may imply a level of
understanding that is not present, and may discourage questions,
v Write all of the consent form except the consent section in the second person (“you are
asked to”) rather than first person or third person.
v The consent section should be written in first person (“I consent to…”).
v Avoid wording that is, or may seem to be, coercive or overly reassuring to a potential
subject.
v Do not make claims of safety or efficacy for investigational articles or procedures.
v Try to avoid the use of the terms “treatment,” “therapy” or “therapeutic” (because these
words may imply effectiveness).
Consent form elements
The following is a list of the usual elements of a consent form (including elements
required by 21 CFR § 50.25; 45 CFR § 46.116; E 6 GCP 4.8.10).
Introductory Information and Purpose
v Explain the research study and the expected duration of subject participation, and
include the approximate number of subjects involved in the study.
v Reassure readers that it is appropriate to ask questions, and that they may take the
form home for consideration (if appropriate for the given research).
v State clearly that the study is research.

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v State the status of the test article based on the country where the research is being
conducted; for example, in the U.S., drugs are “approved,” vaccines are “licensed,”
and devices are “cleared” or “approved for marketing,” otherwise they should be
designated as “investigational.”
v State the purpose(s) of the research; for example, drug protocols usually test for safety,
tolerability and effectiveness.
v State why the person is being asked to participate in the study; for example, “You are
being asked to participate in this study because you have been diagnosed with…”
Description of Study/Procedures
v Describe the visits and procedures (in agreement with the protocol), indicating which
procedures are experimental.
v Briefly describe the study’s design; for example, “This is a dose escalation study. As
subjects participating in the study tolerate a specific dose level, the new subjects entering
the study will be given a higher dose of the study drug.”
v Explain the method used for determining if subjects will receive study drug or placebo,
the method for assigning them to a group, and explain the chance of assignment to
each group in the study.
v State the number of visits.
v Explain the length of study participation.
v Explain what happens at the visits. It is not necessary to list the procedures visit- by-
visit, as detailed descriptions can result in an unnecessarily long consent form.
v Outline any additional participation requirements such as contraception requirements
or prohibited activities.
Risks and Discomforts
v Describe any reasonably foreseeable risks and discomforts to the subject. Risks and
discomforts must be stated in non-technical, layperson’s language. Provide the risks
related to all drugs required by the protocol, including rescue medications, over-the-
counter analgesics, and approved control group drugs.
v Include the possibility of allergic reactions and that serious allergic reactions can be
life-threatening.
v Describe the risks and discomforts of invasive or unusual procedures, including
protocol- required biopsies.
v Describe the risks and discomforts of blood draws, if subjects will have blood drawn.
v Include a statement explaining that there may be risks of participation and side effects
which are still unknown.
v Whether known or unknown, explain the risks to women who are pregnant or who
become pregnant during the study.
v Include a statement that unknown risks and discomforts are possible; if appropriate,
include unknown risks to an embryo or fetus if a subject (or a subject’s partner) is or
becomes pregnant.
v Where applicable, include the risk that the subject’s condition may worsen while they
are in the study (whether assigned to active drug or placebo).
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v If the study drug will be taken home and there is no childproof packaging or warning
labeling, include a warning to keep it out of reach of children or others who may not be
able to read or understand the label.
Expected Benefits
v Describe any possible benefits to the subject or others; indicate that benefits are not
guaranteed.
v If statements regarding direct benefits of participation are included, they should be
qualified as “possible” or that they “may” occur.
Receipt of procedures and study items may be listed as benefits to the subject, but not
in conjunction with their being “free” or at “reduced cost,” as these statements imply a form
of payment and thus should not be categorized as “benefits.” The FDA Information Sheet
“Guidance for Institutional Review Boards and Clinical Investigators” (1998) states,
“Payment to research subjects for participation in studies is not considered a benefit, it is a
recruitment incentive.” Forms of payment may be referenced elsewhere, but not listed as a
benefit of participation.
Alternatives
v Describe appropriate alternative treatments or procedures, if available.
v List several alternatives to participation if they exist; alternatives may include
alternative drugs or therapy, palliative care, hospice care, etc.
v The consent form may say, “Your study doctor will discuss these with you.”
v The section on alternatives should include a brief summary of the risks and benefits of
the alternatives.
Costs
v Describe any known or anticipated costs to the subject. State who is responsible for
the costs of the study-related items such as medications, procedures, device, visits,
hospitalization and treatment for possible side effects.
v Indicate which procedures and items will be provided at no charge.
v If insurance will be billed for anything, include information about possible costs to the
subject or their insurance. If anything is being billed to insurance, discuss what happens
if the insurance does not pay.
Payment for Participation
v Describe the planned prorated payment for participation, if any.
v Any money or other incentive of monetary value should be listed in this section rather
than the benefit section.
v If subjects are to be paid, state specifically for which visits subjects will receive payment
and when such payment will be made; for example, “payment will be made at the end
of each study visit,” “payment will be made at the end of the last study visit” or “payment
will be made within one month after the last study visit.” Be as specific as possible to
minimize confusion. Consider whether any aspects of the total amount or the proration
plan may be coercive or unduly persuasive (WIRB does not routinely allow more than
half the total payment to be assigned to the last visit). The Board may require revision
of the payment or payment schedule.
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v Compensation for Injury
v Outline the plans for compensation and/or medical treatment for research-related injury
or illness, including who will be responsible for the costs.
v Explain what will happen if the subject gets injured. Explain how they will get treatment.
v Clearly state who will pay for treatment if the subject is harmed.
v Address what will happen if the subject’s insurance is billed for the treatment, but
refuses to pay.
WIRB requires that the clinical trials agreement (CTA) between the sponsor and the
investigator (or investigator’s institution) and the approved consent form do not conflict
with each other regarding the compensation for injury. For example, if your CTA indicates
that expenses for treatment of research related injury will be paid, the consent form must
state this as well. Before submitting a request for review of a new research project to WIRB,
please consider what method you will use to ensure that no subjects are enrolled unless the
CTA and the WIRB-approved consent form are in agreement. WIRB accepts a variety of
plans, for example:
v The research is minimal risk research for which compensation for injury language in
the consent form is not necessary.
v There is no CTA for the research.
v The research is funded by a government agency (such as NIH) that does not offer
compensation for injury.
v Upon receipt of WIRB approval documents, the investigator will check the CTA against
the WIRB-approved consent form and resolve any conflicts via a request for a consent
form modification to WIRB and/or a modified CTA before enrolling subjects.
v The sponsor or CRO may agree to review the WIRB-approved consent document and
resolve any conflicts via a request for a consent form modification to WIRB and/or a
modified CTA before authorizing enrollment at this site. WIRB requires the name and
signature of the sponsor or CRO representative, or written correspondence from the
sponsor or CRO indicating who will take this responsibility.
v The PI’s hospital, university or medical center has a contract with WIRB for IRB
services, and it has an established process for ensuring that the compensation for injury
language in the CTA and in the consent form do not conflict.
v The PI’s hospital, university or medical center has an established process for ensuring
that the compensation for injury language in the CTA and in the consent form do not
conflict. (Submitters must provide a description of the process.)
v Sites may also submit plans that differ from any of the plans outlined above.
Questions to be ask
Regulations require that a contact be provided for each of the following types of questions.
v Questions about the research.
v Questions about research-related injury or illness (the Board prefers a physician be
listed as the contact for injury or illness) or study problems.
v Questions about their rights as research subjects (list WIRB and, if desired, a local or

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 institution IRB contact).
v Voluntary Participation/Withdrawal
v State that the subject’s participation is voluntary and that a subject may withdraw at
any time for any reason.
v State that the subject’s decision not to participate or to withdraw from the research
early will involve no penalty or loss of benefits to which the subject is otherwise entitled.
v State that the subject’s participation may be ended by the study doctor or sponsor at
any time for any reason without the subject’s consent. Include any specific reasons
cited in the protocol. General reasons may also be included. Please note: the FDA may
stop the research, but will not stop the participation of an individual subject.
v Include information on any risks involved with withdrawing early; for example, the
need to taper the study drug, obtain follow-up, be placed on standard medication, etc.
v Indicate that subjects who withdraw after the start of the study may be asked to return
for a final visit and final study procedures, and must return the study drug.
Trial Registration
A new rule for informed consent was announced in the Federal Register: January 4,
2011 (Volume 76, Number 2) Page 256-270. The compliance date is March 7, 2012 for clinical
trials that are initiated on or after the compliance date. As of that date, the following statement
must be included in consent forms for “applicable clinical trials’’ as defined in FDAAA, 42
U.S.C. 282(j)(1)(A), section 402(j)(1)(A) of the PHS Act, and any relevant regulation.
“A description of this clinical trial will be available on http://www.Clinical Trials.gov,
as required by U.S. Law. This Web site will not include information that can identify you. At
most, the Web site will include a summary of the results. You can search this Web site at any
time.’’
Since this wording is only required for certain types of clinical trials, and only for
those initiated on or after the compliance date, WIRB will not be automatically including
the text in all existing and new consent forms. Individuals that wish to have the text in them
consent forms must request it. As the compliance date nears, our submission forms will be
revised to collect the information needed to include the text in consent forms when
appropriate.
Other
v Explain that significant new information that may be related to the subject’s willingness
to remain in the research will be provided to the subject.
v Identify the source of funding for the research.
v Disclose conflicts of interest (financial and otherwise).
v State that the subject will receive a copy of the signed and dated consent form.
Consent
This section changes to first person for emphasis; for example, “I voluntarily agree…”
or “I have...”
v Include a statement of the subject’s consent to participate, as well as an authorization
to release medical (or research, as appropriate) records to the parties in the HIPAA
authorization (or confidentiality) section, if applicable; and a statement that the subject
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 is not giving up any legal rights by signing the consent form.
v Include a statement that the subject has read the information in the consent form or had
it read to her/him (as appropriate); however, don’t include statements which imply a
level of comprehension, such as “I understand…”
v Include a statement that the subject’s questions have been answered.
v Signatures and Dates
v Include appropriate signature and date lines for consent as applicable.
v Include a space for the person conducting the informed consent discussion to sign
(required by ICH).
v Provide a line for the investigator to sign if desired by researcher or sponsor; however,
this is not a WIRB requirement.
Pregnant Partner Consent
Many protocols now include instructions for investigators to collect data on the outcome
of pregnancies that occur in partners of male subjects. WIRB follows 45 CFR 46, which
defines research as use of private, identifiable information for research purposes. Since
investigators would be obtaining private information from the pregnant partner and infant,
the partner would be a subject in the research. Investigators must obtain consent from the
pregnant partner before any data collection can occur, and WIRB requires a consent form to
be submitted for these subjects if a pregnancy occurs.
If plans for obtaining consent from the pregnant partner (or a request for a consent
waiver) are not submitted at initial review, the Board may approve the research, but send a
letter reminding the investigator and sponsor that pregnant partners and their infants cannot
be followed-up until WIRB approves a consent plan for them. Please note that no action is
necessary until such time as a pregnancy occurs.
A sample consent form template for obtaining consent from partners who become
pregnant and for collecting data about their infants is available in Appendix 4 of this document
and on the Download Forms page of www.wirb.com. The template consent form cannot be
used without WIRB approval.

GCP obligations of Investigators, sponsors & Monitors

Investigator
Investigator’s Qualifications and Agreements
The investigator(s) should be qualified by education, training, and experience to assume
responsibility for the proper conduct of the trial, should meet all the qualifications specified
by the applicable regulatory requirement(s), and should provide evidence of such
qualifications through up-to-date curriculum vitae and/or other relevant documentation
requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies).
The investigator should be thoroughly familiar with the appropriate use of the
investigational product(s), as described in the protocol, in the current Investigator’s Brochure,
in the product information and in other information sources provided by the sponsor.
The investigator should be aware of, and should comply with, GCP and the applicable
regulatory requirements.
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 The investigator/institution should permit monitoring and auditing by the sponsor, and
inspection by the appropriate regulatory authority(ies).
The investigator should maintain a list of appropriately qualified persons to whom the
investigator has delegated significant trial-related duties.
Adequate Resources
The investigator should be able to demonstrate (e.g., based on retrospective data) a
potential for recruiting the required number of suitable subjects within the agreed recruitment
period.
The investigator should have sufficient time to properly conduct and complete the trial
within the agreed trial period.
The investigator should have available an adequate number of qualified staff and
adequate facilities for the foreseen duration of the trial to conduct the trial properly and
safely.
The investigator should ensure that all persons assisting with the trial are adequately
informed about the protocol, the investigational product(s), and their trial-related duties
and functions.
Addendum
The investigator is responsible for supervising any individual or party to whom the
investigator delegates trial-related duties and functions conducted at the trial site.
If the investigator/institution retains the services of any individual or party to perform
trial-related duties and functions, the investigator/institution should ensure this individual
or party is qualified to perform those trial-related duties and functions and should implement
procedures to ensure the integrity of the trial-related duties and functions performed and
any data generated.
Medical Care of Trial Subjects
A qualified physician (or dentist, when appropriate), who is an investigator or a sub-
investigator for the trial, should be responsible for all trial-related medical (or dental)
decisions.
During and following a subject’s participation in a trial, the investigator/institution
should ensure that adequate medical care is provided to a subject for any adverse events,
including clinically significant laboratory values, related to the trial. The investigator/
institution should inform a subject when medical care is needed for inter current illness(es)
of which the investigator becomes aware.
It is recommended that the investigator inform the subject’s primary physician about
the subject’s participation in the trial if the subject has a primary physician and if the subject
agrees to the primary physician being informed.
Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely
from a trial, the investigator should make a reasonable effort to ascertain the reason(s),
while fully respecting the subject’s rights.
Communication with IRB/IEC
Before initiating a trial, the investigator/institution should have written and dated
approval/favorable opinion from the IRB/IEC for the trial protocol, written informed consent
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form, consent form updates, subject recruitment procedures (e.g., advertisements), and any
other written information to be provided to subjects.
As part of the investigator’s/institution’s written application to the IRB/IEC, the
investigator/institution should provide the IRB/IEC with a current copy of the Investigator’s
Brochure. If the Investigator’s Brochure is updated during the trial, the investigator/institution
should supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
During the trial the investigator/institution should provide to the IRB/IEC all documents
subject to review.
Compliance with Protocol
The investigator/institution should conduct the trial in compliance with the protocol
agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was
given approval/favorable opinion by the IRB/IEC. The investigator/institution and the sponsor
should sign the protocol, or an alternative contract, to confirm agreement.
The investigator should not implement any deviation from, or changes of the protocol
without agreement by the sponsor and prior review and documented approval/favorable
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an
immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or
administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).
The investigator, or person designated by the investigator, should document and explain
any deviation from the approved protocol.
The investigator may implement a deviation from, or a change of, the protocol to
eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favorable
opinion. As soon as possible, the implemented deviation or change, the reasons for it, and,
if appropriate, the proposed protocol amendment(s) should be submitted:
(a) To the IRB/IEC for review and approval/favorable opinion,
(b) To the sponsor for agreement and, if required,
(c) To the regulatory authority(ies).
Investigational Product(s)
Responsibility for investigational product(s) accountability at the trial site(s) rests with
the investigator/institution.
Where allowed/required, the investigator/institution may/should assign some or all of
the investigator’s/institution’s duties for investigational product(s) accountability at the trial
site(s) to an appropriate pharmacist or another appropriate individual who is under the
supervision of the investigator/institution.
The investigator/institution and/or a pharmacist or other appropriate individual, who
is designated by the investigator/institution, should maintain records of the product’s delivery
to the trial site, the inventory at the site, the use by each subject, and the return to the
sponsor or alternative disposition of unused product(s). These records should include dates,
quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers
assigned to the investigational product(s) and trial subjects. Investigators should maintain
records that document adequately that the subjects were provided the doses specified by the
protocol and reconcile all investigational product(s) received from the sponsor.
The investigational product(s) should be stored as specified by the sponsor (see 5.13.2
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and 5.14.3) and in accordance with applicable regulatory requirement(s).
The investigator should ensure that the investigational product(s) are used only in
accordance with the approved protocol.
The investigator, or a person designated by the investigator/institution, should explain
the correct use of the investigational product(s) to each subject and should check, at intervals
appropriate for the trial, that each subject is following the instructions properly.
Randomization Procedures and Unblinding
The investigator should follow the trial’s randomization procedures, if any, and should
ensure that the code is broken only in accordance with the protocol. If the trial is blinded,
the investigator should promptly document and explain to the sponsor any premature
unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the
investigational product(s).
Informed Consent of Trial Subjects
In obtaining and documenting informed consent, the investigator should comply with
the applicable regulatory requirement(s), and should adhere to GCP and to the ethical
principles that have their origin in the Declaration of Helsinki. Prior to the beginning of the
trial, the investigator should have the IRB/IEC’s written approval/favorable opinion of the
written informed consent form and any other written information to be provided to subjects.
The written informed consent form and any other written information to be provided to
subjects should be revised whenever important new information becomes available that may
be relevant to the subject’s consent. Any revised written informed consent form, and written
information should receive the IRB/IEC’s approval/favorable opinion in advance of use.
The subject or the subject’s legally acceptable representative should be informed in a timely
manner if new information becomes available that may be relevant to the subject’s willingness
to continue participation in the trial. The communication of this information should be
documented.
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject
to participate or to continue to participate in a trial.
None of the oral and written information concerning the trial, including the written
informed consent form, should contain any language that causes the subject or the subject’s
legally acceptable representative to waive or to appear to waive any legal rights, or that
releases or appears to release the investigator, the institution, the sponsor, or their agents
from liability for negligence.
The investigator, or a person designated by the investigator, should fully inform the
subject or, if the subject is unable to provide informed consent, the subject’s legally acceptable
representative, of all pertinent aspects of the trial including the written information and the
approval/ favorable opinion by the IRB/IEC.
The language used in the oral and written information about the trial, including the
written informed consent form, should be as non-technical as practical and should be
understandable to the subject or the subject’s legally acceptable representative and the
impartial witness, where applicable.
Before informed consent may be obtained, the investigator, or a person designated by
the investigator, should provide the subject or the subject’s legally acceptable representative
ample time and opportunity to inquire about details of the trial and to decide whether or not
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to participate in the trial. All questions about the trial should be answered to the satisfaction
of the subject or the subject’s legally acceptable representative.
Prior to a subject’s participation in the trial, the written informed consent form should
be signed and personally dated by the subject or by the subject’s legally acceptable
representative, and by the person who conducted the informed consent discussion.
If a subject is unable to read or if a legally acceptable representative is unable to read,
an impartial witness should be present during the entire informed consent discussion. After
the written informed consent form and any other written information to be provided to
subjects, is read and explained to the subject or the subject’s legally acceptable representative,
and after the subject or the subject’s legally acceptable representative has orally consented
to the subject’s participation in the trial and, if capable of doing so, has signed and personally
dated the informed consent form, the witness should sign and personally date the consent
form. By signing the consent form, the witness attests that the information in the consent
form and any other written information was accurately explained to, and apparently
understood by, the subject or the subject’s legally acceptable representative, and that informed
consent was freely given by the subject or the subject’s legally acceptable representative.
Both the informed consent discussion and the written informed consent form and any
other written information to be provided to subjects should include explanations of the
following:
(a) That the trial involves research.
(b) The purpose of the trial.
(c) The trial treatment(s) and the probability for random assignment to each treatment.
(d) The trial procedures to be followed, including all invasive procedures.
(e) The subject’s responsibilities.
(f) Those aspects of the trial that is experimental.
(g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable,
to an embryo, fetus, or nursing infant.
(h) The reasonably expected benefits. When there is no intended clinical benefit to the
subject, the subject should be made aware of this.
(i) The alternative procedure(s) or course(s) of treatment that may be available to the
subject, and their important potential benefits and risks.
(j) The compensation and/or treatment available to the subject in the event of trial-related
injury.
(k) The anticipated prorated payment, if any, to the subject for participating in the trial.
(l) The anticipated expenses, if any, to the subject for participating in the trial.
(m) That the subject’s participation in the trial is voluntary and that the subject may refuse
to participate or withdraw from the trial, at any time, without penalty or loss of benefits
to which the subject is otherwise entitled.
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will
be granted direct access to the subject’s original medical records for verification of
clinical trial procedures and/or data, without violating the confidentiality of the subject,
to the extent permitted by the applicable laws and regulations and that, by signing a

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 written informed consent form, the subject or the subject’s legally acceptable
representative is authorizing such access.
(o) That records identifying the subject will be kept confidential and, to the extent permitted
by the applicable laws and/or regulations, will not be made publicly available. If the
results of the trial are published, the subject’s identity will remain confidential.
(p) That the subject or the subject’s legally acceptable representative will be informed in a
timely manner if information becomes available that may be relevant to the subject’s
willingness to continue participation in the trial.
(q) The person(s) to contact for further information regarding the trial and the rights of
trial subjects, and whom to contact in the event of trial-related injury.
(r) The foreseeable circumstances and/or reasons under which the subject’s participation
in the trial may be terminated.
(s) The expected duration of the subject’s participation in the trial.
(t) The approximate number of subjects involved in the trial.
Prior to participation in the trial, the subject or the subject’s legally acceptable
representative should receive a copy of the signed and dated written informed consent form
and any other written information provided to the subjects. During a subject’s participation
in the trial, the subject or the subject’s legally acceptable representative should receive a
copy of the signed and dated consent form updates and a copy of any amendments to the
written information provided to subjects.
When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only
be enrolled in the trial with the consent of the subject’s legally acceptable representative
(e.g., minors, or patients with severe dementia), the subject should be informed about the
trial to the extent compatible with the subject’s understanding and, if capable, the subject
should sign and personally date the written informed consent.
Except as described in 4.8.14, a non-therapeutic trial (i.e. a trial in which there is no
anticipated direct clinical benefit to the subject), should be conducted in subjects who
personally give consent and who sign and date the written informed consent form.
Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable
representative provided the following conditions are fulfilled:
(a) The objectives of the trial cannot be met by means of a trial in subjects who can give
informed consent personally.
(b) The foreseeable risks to the subjects are low.
(c) The negative impact on the subject’s well-being is minimized and low.
(d) The trial is not prohibited by law.
(e) The approval/favorable opinion of the IRB/IEC are expressly sought on the inclusion
of such subjects, and the written approval/ favorable opinion covers this aspect.
Such trials, unless an exception is justified, should be conducted in patients having a
disease or condition for which the investigational product is intended. Subjects in these
trials should be particularly closely monitored and should be withdrawn if they appear to be
unduly distressed.
In emergency situations, when prior consent of the subject is not possible, the consent
of the subject’s legally acceptable representative, if present, should be requested. When
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prior consent of the subject is not possible, and the subject’s legally acceptable representative
is not available, enrolment of the subject should require measures described in the protocol
and/or elsewhere, with documented approval/favorable opinion by the IRB/IEC, to protect
the rights, safety and well-being of the subject and to ensure compliance with applicable
regulatory requirements. The subject or the subject’s legally acceptable representative should
be informed about the trial as soon as possible and consent to continue and other consent as
appropriate (see 4.8.10) should be requested.
Records and Reports
Addendum
The investigator/institution should maintain adequate and accurate source documents
and trial records that include all pertinent observations on each of the site’s trial subjects.
Source data should be attributable, legible, contemporaneous, original, accurate, and
complete. Changes to source data should be traceable, should not obscure the original entry,
and should be explained if necessary (e.g., via an audit trail).
The investigator should ensure the accuracy, completeness, legibility, and timeliness
of the data reported to the sponsor in the CRFs and in all required reports.
Data reported on the CRF, that are derived from source documents, should be consistent
with the source documents or the discrepancies should be explained.
Any change or correction to a CRF should be dated, initialed, and explained (if
necessary) and should not obscure the original entry (i.e. an audit trail should be maintained);
this applies to both written and electronic changes or corrections (see 5.18.4 (n)). Sponsors
should provide guidance to investigators and/or the investigators’ designated representatives
on making such corrections. Sponsors should have written procedures to assure that changes
or corrections in CRFs made by sponsor’s designated representatives are documented, are
necessary, and are endorsed by the investigator. The investigator should retain records of
the changes and corrections.
The investigator/institution should maintain the trial documents as specified in Essential
Documents for the Conduct of a Clinical Trial (see 8.) and as required by the applicable
regulatory requirement(s). The investigator/institution should take measures to prevent
accidental or premature destruction of these documents.
Essential documents should be retained until at least 2 years after the last approval of
a marketing application in an ICH region and until there are no pending or contemplated
marketing applications in an ICH region or at least 2 years have elapsed since the formal
discontinuation of clinical development of the investigational product. These documents
should be retained for a longer period however if required by the applicable regulatory
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to
inform the investigator/institution as to when these documents no longer need to be retained
(see 5.5.12).
The financial aspects of the trial should be documented in an agreement between the
sponsor and the investigator/institution.
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/
institution should make available for direct access all requested trial-related records.
Progress Reports

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 The investigator should submit written summaries of the trial status to the IRB/IEC
annually, or more frequently, if requested by the IRB/IEC.
The investigator should promptly provide written reports to the sponsor, the IRB/IEC
(see 3.3.8) and, where applicable, the institution on any changes significantly affecting the
conduct of the trial, and/or increasing the risk to subjects.
Safety Reporting
All serious adverse events (SAEs) should be reported immediately to the sponsor except
for those SAEs that the protocol or other document (e.g., Investigator’s Brochure) identifies
as not needing immediate reporting. The immediate reports should be followed promptly by
detailed, written reports. The immediate and follow-up reports should identify subjects by
unique code numbers assigned to the trial subjects rather than by the subjects’ names, personal
identification numbers, and/or addresses. The investigator should also comply with the
applicable regulatory requirement(s) related to the reporting of unexpected serious adverse
drug reactions to the regulatory authority(ies) and the IRB/IEC.
Adverse events and/or laboratory abnormalities identified in the protocol as critical to
safety evaluations should be reported to the sponsor according to the reporting requirements
and within the time periods specified by the sponsor in the protocol.
For reported deaths, the investigator should supply the sponsor and the IRB/IEC with
any additional requested information (e.g., autopsy reports and terminal medical reports).
Premature Termination or Suspension of a Trial
If the trial is prematurely terminated or suspended for any reason, the investigator/
institution should promptly inform the trial subjects, should assure appropriate therapy and
follow-up for the subjects, and, where required by the applicable regulatory requirement(s),
should inform the regulatory authority(ies). In addition:
If the investigator terminates or suspends a trial without prior agreement of the sponsor,
the investigator should inform the institution where applicable, and the investigator/institution
should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and
the IRB/IEC a detailed written explanation of the termination or suspension.
If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly
inform the institution where applicable and the investigator/institution should promptly
inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination
or suspension.
If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial (see
3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the
investigator/institution should promptly notify the sponsor and provide the sponsor with a
detailed written explanation of the termination or suspension.
Final Report(s) by Investigator
Upon completion of the trial, the investigator, where applicable, should inform the
institution; the investigator/institution should provide the IRB/IEC with a summary of the
trial’s outcome, and the regulatory authority(ies) with any reports required.
Sponsor
Addendum
Quality Management
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 The sponsor should implement a system to manage quality throughout all stages of the
trial process.
Sponsors should focus on trial activities essential to ensuring human subject protection
and the reliability of trial results. Quality management includes the design of efficient clinical
trial protocols and tools and procedures for data collection and processing, as well as the
collection of information that is essential to decision making.
The methods used to assure and control the quality of the trial should be proportionate
to the risks inherent in the trial and the importance of the information collected. The sponsor
should ensure that all aspects of the trial are operationally feasible and should avoid
unnecessary complexity, procedures, and data collection. Protocols, case report forms, and
other operational documents should be clear, concise, and consistent.
The quality management system should use a risk-based approach as described below.
Critical Process and Data Identification
During protocol development, the sponsor should identify those processes and data
that are critical to ensure human subject protection and the reliability of trial results.
Risk Identification
The sponsor should identify risks to critical trial processes and data. Risks should be
considered at both the system level (e.g., standard operating procedures, computerized
systems, personnel) and clinical trial level (e.g., trial design, data collection, informed consent
process).
Risk Evaluation
The sponsor should evaluate the identified risks, against existing risk controls by
considering:
(a) The likelihood of errors occurring.
(b) The extent to which such errors would be detectable.
c) The impact of such errors on human subject protection and reliability of trial results.
Risk Control
The sponsor should decide which risks to reduce and/or which risks to accept. The
approach used to reduce risk to an acceptable level should be proportionate to the significance
of the risk. Risk reduction activities may be incorporated in protocol design and
implementation, monitoring plans, agreements between parties defining roles and
responsibilities, systematic safeguards to ensure adherence to standard operating procedures,
and training in processes and procedures.
Predefined quality tolerance limits should be established, taking into consideration the
medical and statistical characteristics of the variables as well as the statistical design of the
trial, to identify systematic issues that can impact subject safety or reliability of trial results.
Detection of deviations from the predefined quality tolerance limits should trigger an
evaluation to determine if action is needed.
Risk Communication
The sponsor should document quality management activities. The sponsor should
communicate quality management activities to those who are involved in or affected by

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such activities, to facilitate risk review and continual improvement during clinical trial
execution.
Risk Review
The sponsor should periodically review risk control measures to ascertain whether the
implemented quality management activities remain effective and relevant, taking into account
emerging knowledge and experience.
Risk Reporting
The sponsor should describe the quality management approach implemented in the
trial and summarize important deviations from the predefined quality tolerance limits and
remedial actions taken in the clinical study report (ICH E3, Section 9.6 Data Quality
Assurance).
Quality Assurance and Quality Control
The sponsor is responsible for implementing and maintaining quality assurance and
quality control systems with written SOPs to ensure that trials are conducted and data are
generated, documented (recorded), and reported in compliance with the protocol, GCP, and
the applicable regulatory requirement(s).
The sponsor is responsible for securing agreement from all involved parties to ensure
direct access (see 1.21) to all trial related sites, source data/documents, and reports for the
purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign
regulatory authorities.
Quality control should be applied to each stage of data handling to ensure that all data
are reliable and have been processed correctly.
Agreements, made by the sponsor with the investigator/institution and any other parties
involved with the clinical trial, should be in writing, as part of the protocol or in a separate
agreement.
Contract Research Organization (CRO)
A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to
a CRO, but the ultimate responsibility for the quality and integrity of the trial data always
resides with the sponsor. The CRO should implement quality assurance and quality control.
Any trial-related duty and function that is transferred to and assumed by a CRO should
be specified in writing.
Addendum
The sponsor should ensure oversight of any trial-related duties and functions carried
out on its behalf, including trial-related duties and functions that are subcontracted to another
party by the sponsor’s contracted CRO(s).
Any trial-related duties and functions not specifically transferred to and assumed by a
CRO are retained by the sponsor.
All references to a sponsor in this guideline also apply to a CRO to the extent that a
CRO has assumed the trial related duties and functions of a sponsor.
Medical Expertise
The sponsor should designate appropriately qualified medical personnel who will be

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readily available to advise on trial related medical questions or problems. If necessary, outside
consultant(s) may be appointed for this purpose.
Trial Design
The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical
pharmacologists, and physicians) as appropriate, throughout all stages of the trial process,
from designing the protocol and CRFs and planning the analyses to analyzing and preparing
interim and final clinical trial reports.
For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the
ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate
ICH guidance on trial design, protocol and conduct.
Trial Management, Data Handling, and Record Keeping
The sponsor should utilize appropriately qualified individuals to supervise the overall
conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses,
and to prepare the trial reports.
The sponsor may consider establishing an independent data-monitoring committee
(IDMC) to assess the progress of a clinical trial, including the safety data and the critical
efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify,
or stop a trial. The IDMC should have written operating procedures and maintain written
records of all its meetings.
When using electronic trial data handling and/or remote electronic trial data systems,
the sponsor should:
a) Ensure and document that the electronic data processing system(s) conforms to the
sponsor ’s established requirements for completeness, accuracy, reliability, and
consistent intended performance (i.e. validation).
ADDENDUM
b) The sponsor should base their approach to validation of such systems on a risk
assessment that takes into consideration the intended use of the system and the potential
of the system to affect human subject protection and reliability of trial results.
c) Maintains SOPs for using these systems.
Addendum
d) The SOPs should cover system setup, installation, and use. The SOPs should describe
system validation and functionality testing, data collection and handling, system
maintenance, system security measures, change control, data backup, recovery,
contingency planning, and decommissioning. The responsibilities of the sponsor,
investigator, and other parties with respect to the use of these computerized systems
should be clear, and the users should be provided with training in their use.
e) Ensure that the systems are designed to permit data changes in such a way that the data
changes are documented and that there is no deletion of entered data (i.e. maintain an
audit trail, data trail, edit trail).
f) Maintain a security system that prevents unauthorized access to the data.
g) Maintain a list of the individuals who are authorized to make data changes (see 4.1.5
and 4.9.3).

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h) Safeguard the blinding, if any (e.g. maintain the blinding during data entry and
processing).
Addendum
Ensure the integrity of the data including any data that describe the context, content,
and structure. This is particularly important when making changes to the computerized
systems, such as software upgrades or migration of data.
If data are transformed during processing, it should always be possible to compare the
original data and observations with the processed data.
The sponsor should use an unambiguous subject identification code (see 1.58) that
allows identification of all the data reported for each subject.
The sponsor, or other owners of the data, should retain all of the sponsor-specific
essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a
Clinical Trial).
The sponsor should retain all sponsor-specific essential documents in conformance
with the applicable regulatory requirement(s) of the country(ies) where the product is
approved, and/or where the sponsor intends to apply for approval(s).
If the sponsor discontinues the clinical development of an investigational product (i.e.
for any or all indications, routes of administration, or dosage forms), the sponsor should
maintain all sponsor-specific essential documents for at least 2 years after formal
discontinuation or in conformance with the applicable regulatory requirement(s).
If the sponsor discontinues the clinical development of an investigational product, the
sponsor should notify all the trial investigators/institutions and all the regulatory authorities.
Any transfer of ownership of the data should be reported to the appropriate
authority(ies), as required by the applicable regulatory requirement(s).
The sponsor specific essential documents should be retained until at least 2 years after
the last approval of a marketing application in an ICH region and until there are no pending
or contemplated marketing applications in an ICH region or at least 2 years have elapsed
since the formal discontinuation of clinical development of the investigational product. These
documents should be retained for a longer period however if required by the applicable
regulatory requirement(s) or if needed by the sponsor.
The sponsor should inform the investigator(s)/institution(s) in writing of the need for
record retention and should notify the investigator(s)/institution(s) in writing when the trial
related records are no longer needed.
Investigator Selection
The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator
should be qualified by training and experience and should have adequate resources (see 4.1,
4.2) to properly conduct the trial for which the investigator is selected. If organization of a
coordinating committee and/or selection of coordinating investigator(s) are to be utilized in
multicenter trials, their organization and/or selection is the sponsor’s responsibility.
Before entering an agreement with an investigator/institution to conduct a trial, the
sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date
Investigator’s Brochure, and should provide sufficient time for the investigator/institution
to review the protocol and the information provided.
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 The sponsor should obtain the investigators/institution’s agreement:
a) to conduct the trial in compliance with GCP, with the applicable regulatory
requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and given
approval/favorable opinion by the IRB/IEC (see 4.5.1);
b) to comply with procedures for data recording/reporting;
c) to permit monitoring, auditing and inspection (see 4.1.4) and
d) to retain the trial related essential documents until the sponsor informs the investigator/
institution these documents are no longer needed (see 4.9.4 and 5.5.12).
e) The sponsor and the investigator/institution should sign the protocol, or an alternative
document, to confirm this agreement.
Allocation of Responsibilities
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-
related duties and functions.
Compensation to Subjects and Investigators
If required by the applicable regulatory requirement(s), the sponsor should provide
insurance or should indemnify (legal and financial coverage) the investigator/the institution
against claims arising from the trial, except for claims that arise from malpractice and/or
negligence.
The sponsor’s policies and procedures should address the costs of treatment of trial
subjects in the event of trial-related injuries in accordance with the applicable regulatory
requirement(s).
When trial subjects receive compensation, the method and manner of compensation
should comply with applicable regulatory requirement(s).
Financing
The financial aspects of the trial should be documented in an agreement between the
sponsor and the investigator/institution.
Notification/Submission to Regulatory Authority(ies)
Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator,
if required by the applicable regulatory requirement(s)) should submit any required
application(s) to the appropriate authority(ies) for review, acceptance, and/or permission
(as required by the applicable regulatory requirement(s)) to begin the trial(s). Any notification/
submission should be dated and contain sufficient information to identify the protocol.
Confirmation of Review by IRB/IEC
The sponsor should obtain from the investigator/institution:
a) The name and address of the investigator’s/institution’s IRB/IEC.
b) A statement obtained from the IRB/IEC that it is organized and operates according to
GCP and the applicable laws and regulations.
c) Documented IRB/IEC approval/favorable opinion and, if requested by the sponsor, a
current copy of protocol, written informed consent form(s) and any other written
information to be provided to subjects, subject recruiting procedures, and documents
related to payments and compensation available to the subjects, and any other documents
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 that the IRB/IEC may have requested.
If the IRB/IEC conditions its approval/favorable opinion upon change(s) in any aspect
of the trial, such as modification(s) of the protocol, written informed consent form and any
other written information to be provided to subjects, and/or other procedures, the sponsor
should obtain from the investigator/institution a copy of the modification(s) made and the
date approval/favorable opinion was given by the IRB/IEC.
The sponsor should obtain from the investigator/institution documentation and dates
of any IRB/IEC re-approvals/re-evaluations with favorable opinion, and of any withdrawals
or suspensions of approval/favorable opinion.
Information on Investigational Product(s)
When planning trials, the sponsor should ensure that sufficient safety and efficacy data
from nonclinical studies and/or clinical trials are available to support human exposure by
the route, at the dosages, for the duration, and in the trial population to be studied.
The sponsor should update the Investigator’s Brochure as significant new information
becomes available (see 7. Investigator’s Brochure).
Manufacturing, Packaging, Labelling, and Coding Investigational
Product(s)
The sponsor should ensure that the investigational product(s) (including active
comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of
development of the product(s), is manufactured in accordance with any applicable GMP,
and is coded and labelled in a manner that protects the blinding, if applicable. In addition,
the labelling should comply with applicable regulatory requirement(s).
The sponsor should determine, for the investigational product(s), acceptable storage
temperatures, storage conditions (e.g. protection from light), storage times, reconstitution
fluids and procedures, and devices for product infusion, if any. The sponsor should inform
all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these
determinations.
The investigational product(s) should be packaged to prevent contamination and
unacceptable deterioration during transport and storage.
In blinded trials, the coding system for the investigational product(s) should include a
mechanism that permits rapid identification of the product(s) in case of a medical emergency,
but does not permit undetectable breaks of the blinding.
If significant formulation changes are made in the investigational or comparator
product(s) during the course of clinical development, the results of any additional studies of
the formulated product(s) (e.g. stability, dissolution rate, bio-availability) needed to assess
whether these changes would significantly alter the pharmacokinetic profile of the product
should be available prior to the use of the new formulation in clinical trials.
Supplying and Handling Investigational Product(s)
The sponsor is responsible for supplying the investigator(s)/institution(s) with the
investigational product(s).
The sponsor should not supply an investigator/institution with the investigational
product(s) until the sponsor obtains all required documentation (e.g. approval/favorable
opinion from IRB/IEC and regulatory authority(ies)).
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 The sponsor should ensure that written procedures include instructions that the
investigator/institution should follow for the handling and storage of investigational
product(s) for the trial and documentation thereof. The procedures should address adequate
and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects,
and return of unused investigational product(s) to the sponsor (or alternative disposition if
authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).
The sponsor should:
a) Ensure timely delivery of investigational product(s) to the investigator(s).
b) Maintain records that document shipment, receipt, disposition, return, and destruction
of the investigational product(s) (see 8. Essential Documents for the Conduct of a
Clinical Trial).
c) Maintain a system for retrieving investigational products and documenting this retrieval
(e.g. for deficient product recall, reclaim after trial completion, expired product
reclaims).
d) Maintain a system for the disposition of unused investigational product(s) and for the
documentation of this disposition.
The sponsor should:
a) Maintain sufficient quantities of the investigational product(s) used in the trials to
reconfirm specifications, should this become necessary, and maintain records of batch
sample analyses and characteristics. To the extent stability permits, samples
b) Should be retained either until the analyses of the trial data are complete or as required
by the applicable regulatory requirement(s), whichever represents the longer retention
period.
Record Access
The sponsor should ensure that it is specified in the protocol or other written agreement
that the investigator(s)/institution(s) provide direct access to source data/documents for trial-
related monitoring, audits, IRB/IEC review, and regulatory inspection.
The sponsor should verify that each subject has consented, in writing, to direct access
to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and
regulatory inspection.
Safety Information
The sponsor is responsible for the ongoing safety evaluation of the investigational
product(s).
The sponsor should promptly notify all concerned investigator(s)/institution(s) and the
regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact
the conduct of the trial, or alter the IRB/IEC’s approval/favorable opinion to continue the
trial.
Adverse Drug Reaction Reporting
The s ponsor s hould expedi te the reporti ng to al l concerned invest igator(s )/
institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of
all adverse drug reactions (ADRs) that are both serious and unexpected.

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 Such expedited reports should comply with the applicable regulatory requirement(s)
and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards
for Expedited Reporting.
The sponsor should submit to the regulatory authority(ies) all safety updates and periodic
reports, as required by applicable regulatory requirement(s).
Monitor
Monitoring
Purpose
The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from source documents.
(c) The conduct of the trial is in compliance with the currently approved protocol/
amendment(s), with GCP, and with the applicable regulatory requirement(s).
Selection and Qualifications of Monitors
(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the scientific and/or clinical
knowledge needed to monitor the trial adequately. A monitor’s qualifications should
be documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the protocol,
written informed consent form and any other written information to be provided to
subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
Extent and Nature of Monitoring The sponsor should ensure that the trials are adequately
monitored. The sponsor should determine the appropriate extent and nature of monitoring.
The determination of the extent and nature of monitoring should be based on considerations
such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial.
In general, there is a need for on-site monitoring, before, during, and after the trial; however,
in exceptional circumstances the sponsor may determine that central monitoring in
conjunction with procedures such as investigators’ training and meetings, and extensive
written guidance can assure appropriate conduct of the trial in accordance with GCP.
Statistically controlled sampling may be an acceptable method for selecting the data to be
verified.
Addendum
The sponsor should develop a systematic, prioritized, risk-based approach to monitoring
clinical trials. The flexibility in the extent and nature of monitoring described in this section
is intended to permit varied approaches that improve the effectiveness and efficiency of
monitoring. The sponsor may choose on-site monitoring, a combination of on-site and
centralized monitoring, or, where justified, centralized monitoring. The sponsor should
document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).
On-site monitoring is performed at the sites at which the clinical trial is being conducted.
Centralized monitoring is a remote evaluation of accumulating data, performed in a timely
manner, supported by appropriately qualified and trained persons (e.g., data managers,
biostatisticians).

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 Centralized monitoring processes provide additional monitoring capabilities that can
complement and reduce the extent and/or frequency of on-site monitoring and help distinguish
between reliable data and potentially unreliable data.
Review that may include statistical analyses, of accumulating data from centralized
monitoring can be used to:
a) Identify missing data, inconsistent data, data outliers, unexpected lack of variability
and protocol deviations.
b) Examine data trends such as the range, consistency, and variability of data within and
across sites.
c) Evaluate for systematic or significant errors in data collection and reporting at a site or
across sites; or potential data manipulation or data integrity problems.
d) Analyze site characteristics and performance metrics.
e) Select sites and/or processes for targeted on-site monitoring.
Monitor’s Responsibilities.
The monitor(s) in accordance with the sponsor’s requirements should ensure that the
trial is conducted and documented properly by carrying out the following activities when
relevant and necessary to the trial and the trial site:
a. Acting as the main line of communication between the sponsor and the investigator.
b. Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2,
5.6) and remain adequate throughout the trial period, that facilities, including laboratories,
equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate
throughout the trial period.
c. Verifying, for the investigational product(s):
i. That storage times and conditions are acceptable, and that supplies are sufficient
throughout the trial.
ii. That the investigational product(s) are supplied only to subjects who are eligible to
receive it and at the protocol specified dose(s).
iii. Those subjects are provided with necessary instruction on properly using, handling,
storing, and returning the investigational product(s).
iv. That the receipt, use, and return of the investigational product(s) at the trial sites are
controlled and documented adequately.
v. That the disposition of unused investigational product(s) at the trial sites complies
with applicable regulatory requirement(s) and is in accordance with the sponsor.
d. Verifying that the investigator follows the approved protocol and all approved
amendment(s), if any.
e. Verifying that written informed consent was obtained before each subject’s participation
in the trial
f. Ensuring that the investigator receives the current Investigator ’s Brochure, all
documents, and all trial supplies needed to conduct the trial properly and to comply with the
applicable regulatory requirement(s)
g. Ensuring that the investigator and the investigator’s trial staff are adequately informed

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about the trial.
h. Verifying that the investigator and the investigator’s trial staff are performing the
specified trial functions, in accordance with the protocol and any other written agreement
between the sponsor and the investigator/institution, and have not delegated these functions
to unauthorized individuals.
i. Verifying that the investigator is enrolling only eligible subjects.
j. Reporting the subject recruitment rate.
k. Verifying that source documents and other trial records are accurate, complete, kept
up-to-date and maintained.
l. Verifying that the investigator provides all the required reports, notifications,
applications, and submissions, and that these documents are accurate, complete, timely,
legible, dated, and identify the trial.
m. Checking the accuracy and completeness of the CRF entries, source documents and
other trial-related records against each other. The monitor specifically should verify that:
i. The data required by the protocol are reported accurately on the CRFs and are consistent
with the source documents.
ii. Any dose and/or therapy modifications are well documented for each of the trial subjects.
iii. Adverse events, concomitant medications and inter current illnesses are reported in
accordance with the protocol on the CRFs.
iv. Visits that the subjects fail to make, tests that are not conducted, and examinations that
are not performed are clearly reported as such on the CRFs.
v. All withdrawals and dropouts of enrolled subjects from the trial are reported and
explained on the CRFs.
n. Informing the investigator of any CRF entry error, omission, or illegibility. The monitor
should ensure that appropriate corrections, additions, or deletions are made, dated, explained
(if necessary), and initialed by the investigator or by a member of the investigator’s trial
staff who is authorized to initial CRF changes for the investigator. This authorization should
be documented.
o. Determining whether all adverse events (AEs) are appropriately reported within the
time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable
regulatory requirement(s).
p. Determining whether the investigator is maintaining the essential documents (see 8.
Essential Documents for the Conduct of a Clinical Trial).
q. Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory
requirements to the investigator and taking appropriate action designed to prevent recurrence
of the detected deviations.
Monitoring Procedures
The monitor(s) should follow the sponsor’s established written SOPs as well as those
procedures that are specified by the sponsor for monitoring a specific trial.
Monitoring Report
a) The monitor should submit a written report to the sponsor after each trial-site visit or
trial-related communication.
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b) Reports should include the date, site, name of the monitor, and name of the investigator
or other individual(s) contacted.
c) Reports should include a summary of what the monitor reviewed and the monitor’s
statements concerning the significant findings/facts, deviations and deficiencies,
conclusions, actions taken or to be taken and/or actions recommended to secure
compliance.
d) The review and follow-up of the monitoring report with the sponsor should be
documented by the sponsor’s designated representative.
Addendum
a) Reports of on-site and/or centralized monitoring should be provided to the sponsor
(including appropriate management and staff responsible for trial and site oversight)
in a timely manner for review and follow up. Results of monitoring activities should
be documented in sufficient detail to allow verification of compliance with the
monitoring plan. Reporting of centralized monitoring activities should be regular and
may be independent from site visits.
Addendum
Monitoring Plan
The sponsor should develop a monitoring plan that is tailored to the specific human
subject protection and data integrity risks of the trial. The plan should describe the monitoring
strategy, the monitoring responsibilities of all the parties involved, the various monitoring
methods to be used, and the rationale for their use. The plan should also emphasize the
monitoring of critical data and processes. Particular attention should be given to those aspects
that are not routine clinical practice and that require additional training. The monitoring
plan should reference the applicable policies and procedures.
Audit
If or when sponsors perform audits, as part of implementing quality assurance, they
should consider:
Purpose
The purpose of a sponsor’s audit, which is independent of and separate from routine
monitoring or quality control functions, should be to evaluate trial conduct and compliance
with the protocol, SOPs, GCP, and the applicable regulatory requirements.
Selection and Qualification of Auditors
a) The sponsor should appoint individuals, who are independent of the clinical trials/
systems, to conduct audits.
b) The sponsor should ensure that the auditors are qualified by training and experience to
conduct audits properly. An auditor’s qualifications should be documented.
Auditing Procedures
a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in
accordance with the sponsor’s written procedures on what to audit, how to audit, the
frequency of audits, and the form and content of audit reports.
b) The sponsor’s audit plan and procedures for a trial audit should be guided by the
importance of the trial to submissions to regulatory authorities, the number of subjects
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 in the trial, the type and complexity of the trial, the level of risks to the trial subjects,
and any identified problem(s).
c) The observations and findings of the auditor(s) should be documented.
d) To preserve the independence and value of the audit function, the regulatory
authority(ies) should not routinely request the audit reports. Regulatory authority(ies)
may seek access to an audit report on a case by case basis when evidence of serious
GCP non-compliance exists, or in the course of legal proceedings.
e) When required by applicable law or regulation, the sponsor should provide an audit
certificate.
Noncompliance
Noncompl iance wit h the prot ocol, SOP s, GCP, and/ or appl icable regul atory
requirement(s) by an investigator/institution, or by member(s) of the sponsor’s staff should
lead to prompt action by the sponsor to secure compliance.
Addendum
If noncompliance that significantly affects or has the potential to significantly affect
human subject protection or reliability of trial results is discovered, the sponsor should
perform a root cause analysis and implement appropriate corrective and preventive actions.
If the monitoring and/or auditing identify serious and/or persistent noncompliance on
the part of an investigator/institution, the sponsor should terminate the investigator’s/
institution’s participation in the trial. When an investigator’s/institution’s participation is
terminated because of noncompliance, the sponsor should notify promptly the regulatory
authority(ies).
Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor should promptly inform
the investigators/institutions, and the regulatory authority(ies) of the termination or
suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be
informed promptly and provided the reason(s) for the termination or suspension by the sponsor
or by the investigator/institution, as specified by the applicable regulatory requirement(s).
Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the sponsor should ensure
that the clinical trial reports are prepared and provided to the regulatory agency(ies) as
required by the applicable regulatory requirement(s). The sponsor should also ensure that
the clinical trial reports in marketing applications meet the standards of the ICH Guideline
for Structure and Content of Clinical Study Reports. (NOTE: The ICH Guideline for Structure
and Content of Clinical Study Reports specifies that abbreviated study reports may be
acceptable in certain cases.)
Multicenter Trials
For multicenter trials, the sponsor should ensure that: All investigators conduct the
trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the
regulatory authority(ies), and given approval/favorable opinion by the IRB/IEC. The CRFs
are designed to capture the required data at all multicenter trial sites. For those investigators
who are collecting additional data, supplemental CRFs should also be provided that is

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designed to capture the additional data. The responsibilities of coordinating investigator(s)
and the other participating investigators are documented prior to the start of the trial. All
investigators are given instructions on following the protocol, on complying with a uniform
set of standards for the assessment of clinical and laboratory findings, and on completing
the CRFs. Communication between investigators is facilitated
Managing and monitoring clinical trials
Background
Pharmacovigilance is majorly known as drug safety. It is a main integral part of clinical
research. Throughout the product life cycle clinical trials safety and post marketing
pharmacovigilance plays a critical role [1-3]. The word pharmacovigilance is derived from
two words one Pharmakon is a Greek word which means “drug” and another vigilare is a
Latin word which means to keep awake or to keep watch.” Pharmacovigilance is “defined as
the pharmacological science relating to the detection, understanding, assessment and
prevention of adverse effects, particularly long term and short-term adverse effects of
medicines”.
According to WHO Pharmacovigilance (PV) is the pharmacological science relating to
the detection, evaluation, understanding and prevention of adverse effects, especially long
term and short-term side effects of medicines.
Aims of pharmacovigilance
v To improve patient care &safety
v To contribute to assessment of benefit, harm & effectiveness of medicine
v To Identify previously unrecognized adverse effects of the drugs
v To Promote rational & safe use of medicine
v To Promote education & clinical training
v To Identify patient related risk factors of ADR such as dose, age, gender
v Any response to a drug which is unintended, occurs at particular doses
v To diagnose or therapy of disease, or for the modification, of physiological function.
Pharmacovigilance helps in removal of approved and licensed products from the market
because of clinical toxicity, which is caused by adverse drug reactions in the body. Below is
a short note on adverse drug reactions.

Pharmacovigilance - safety monitoring in clinical trials

Clinical monitoring is the oversight and administrative efforts that monitor a
participant’s health and efficacy of the treatment during a clinical trial. Both independent
and government-run grant-funding agencies, such as the National Institutes of Health
( N IH ) [1 ] an d t h e Wo r l d H e al t h O rgan i z at i o n ( W HO ) , r e q ui r e d a t a a n d s a fe t y
monitoring protocols for Phase I and II clinical trials conforming to their standards
Safety monitoring
Safety monitoring of a clinical trial is conducted by an independent physician with
relevant expertise. This is accomplished by review of adverse event, immediately after they
occur, with timely follow-up through resolution. [4]
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 Responsibility for data and safety monitoring depends on the phase of the study and
may be conducted by sponsor or Contract research organization (CRO) staff or contractor,
and/or by the Principal clinical investigator/project manager conducting the study. Regardless
of the method used, monitoring must be performed on a regular basis. Oversight of the
monitoring activity is the responsibility of the sponsor.
Aspect of monitoring
According to the U.S. Food and Drug Administration’s Center of Drug Evaluation and
Research, the top five deficiency categories for site inspections caught by clinical monitors
as reported in the 2001 Report to the Nation [5] are:
v Failure to follow investigation protocol (the procedures and treatment subjects must
undergo, as well as the schedule of assessments)
v Failure to keep adequate and accurate records
v Problems with the informed consent form
v Failure to report adverse events
v Failure to account for the disposition of study drugs
Therefore, the primary goal of clinical trial monitoring is to observe each trial site to
ensure that the standardized operation procedures for the trial are being followed, reporting
and managing any deviations from the investigation plan as they occur. Monitoring plans in
the United States typically also require a clear protocol for reporting adverse/undesirable
effects caused by the treatment to the institutional review board (IRB), the US Food & Drug
Administration (FDA), and the institution funding the research. [3][6] The FDA itself maintains
an Adverse Event Reporting System for such occurrences in clinical trials it oversees in the
United States.
Function of clinical Monitor
Clinical monitors execute the monitoring plan laid out by the sponsors and investigators
of a clinical trial. Monitors may be referred to by many different titles, such as: Clinical
Research Associate, “on-site” monitor, Clinical Research Monitor, Study Site Monitor and
Quality Specialist. The number of clinical monitors depends on the scale and scope of the
trial.
Almost all field monitoring requires regular visits to the site by the clinical research
associate throughout the period of the study. On occasion, an extremely simple, low-risk
study might be monitored almost exclusively by telephone except for the startup and closeout
visits. Since the concept of “low risk” is subjective, this definition should be established in
internal policies and procedures.
Complexity and Monitoring
The level of scrutiny of monitoring varies across studies based on risks and nature of
the trial.
Considerations that affect the design of monitoring plans usually include [6][3]:
v Complexity of the protocol (including toxicity, presence of special populations inside
sample groups, amount of interaction needed, length of treatment, etc.)
v Risk of the treatment
v Disease being evaluated
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v Number of study subjects enrolled at the site
v Number of treatment sites (such as number of clinics with access to and assigning the
treatment)
v Site performance
v Sponsor monitoring standard operating protocols
Several of these factors depend on the phase of the clinical trial—for example, in some
early Phase I studies of drugs whose effects on different individuals are unknown, the monitor
may be required to be present during all or part of a subject’s treatment, while Phase II
investigations usually involve multiple investigation sites [2].
The overall monitoring plan should remain fairly consistent, but the strategy for
individual sites may change considerably during the course of the study depending on study
conditions and site performance.
Adverse Drug Reactions
ADR is a response to drug, which alters the normal physiological function of the body,
factors which causes ADR includes mainly multiple drug therapy, age & gender.
They are mainly two types of ADR
TYPE A: These are common, predictable, dose dependent, they are seldom fatal
TYPE B: These are uncommon, unpredictable, dose independent; they involve relatively
high rates of serious morbidity.
High index of ADRs are to be successfully diagnosed by clinicians, it is the high level
of awareness about the drugs being used. Pharmacovigilance, unify all the information in all
aspects of benefit-risk ratio of drugs in a population. Events that occur when a particular
drug is administered are recorded in the patient’s notes by drug monitoring then an adverse
reaction of the drug and the activity of the drug being monitored; these studies aim to detect
ADR of drugs
Reporting of ADRs after marketing must be actively encouraged and should involve
all those concerned including doctors, pharmacists, nurses, patients and pharmaceutical
companies. To develop and enhance this, a culture of learning about pharmacovigilance for
health care students must be started in their early professional carrier. This will help healthcare
professionals to understand and also create awareness by giving adequate information to
patients at their initial phase of treatment about the potential benefits and risks of the therapy
In the process of development of a new pharmaceutical drug, there are many stages they are
preclinical trials, then clinical trials this includes four phases. In this the first three phase’s
helps in the determination of safety, efficacy and side effects of the developed drug product
respectively, whereas in case of fourth phase post marketing studies are carried out for
determining safety in patients. Thus, post marketing surveillance helps in uplifting the
knowledge of pharmacovigilance.
Post marketing surveillance
Pharmaceutical drug or medical device is monitored often after it has been released in
to the market, Since drugs are approved based of clinical trials which involve relatively
small number of people who do not have any other medical complications, post marketing
surveillance play an important role to know the ADRs of drugs after they have released in to
the market [60-67].

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Approaches by
spontaneous ADR reporting
Prescription event monitoring
Electronic health records
Patient Registers
Spontaneous ADR Reporting
It is necessary to report ADRs to Pharmacovigilance department by doctors, health
care professionals, they are provided with forms where they can notify the suspected ADRs
they detect, these forms are greatly available to health care professionals to encourage the
reporting, it helps in spontaneous reporting for all the drugs, it is affordable method of
detecting rare ADRs. This spontaneous reporting helps to identify many unexpected ADRs,
it helps in withdrawal of many marketed drugs, and information being provided which guide
safer use of the product.
ADRs which occurred by particular drugs should be anal yzed and reported,
Pharmaceutical manufacturers have to communicate with the doctors at the clinical level
regarding the ADRs by
v Changing Medication formula if necessary
v Implementing new prescribing procedures
v Implementing new dispensing procedures
v Educating the professional staff
v Educating Patients
Prescription Event Monitoring
It involves health professionals submitting all the clinical events reported by the patient
to the prescribed new drug.
This method mainly focuses on studying the safety of new medications that are used by
general practitioners in this method.
In this method patients being prescribed by drugs are monitored.
Electronic Health Records
It is a computer stored collection of health information, about one person linked by a
person identifier; it represents the basis for healthcare Information system development [86].
Patient Registers
To bring together patient records, it is time consuming and less expensive
Pharmacovigilance programme of India (PVPI)
It officially starts on 23rd November 2004 at New Delhi, is under the control of CDSCO
(Central Drug Standard Control Organization), Directorate general of health services, Indian
pharmacopeia commission (Ghaziabad). The program is conducting by NCC (National
Coordinating Centre) to ensure that the benefits of use of medicine against the risks.
It was Launched by the MoHFW, Govt. of India in the year 2010 at AIIMS New Delhi

135
 Figure 1: The Pharmacovigilance Frame work

as National Coordinating Centre (NCC). ? The Programme transferred to IPC as NCC in

April, 2011 by a Notification issued by the MoHFW, Govt. of India. ? IPC-PvPI became the
NCC for Materiovigilance Programme of India (MvPI) from July, 2015 ? IPC, NCC-PvPI
became a WHO Collaborating Centre for Pharmacovigilance in Public Health Programmes
& Regulatory services from July, 2017
Objectives:
To monitor ADRs
To create awareness among health care professionals about ADRs
To monitor benefit-risk profile of medicines
Support the CDSCO
Pharmacovigilance in Acts & Rules
Pharmacy Council of India: Pharmacovigilance as one of the subjects in Pharmacy
Under Graduate curriculum
Drugs & Cosmetic Act & Its rules 1945: establishment of Pharmacovigilance cell in
the pharmaceutical industry is mandatory.
National Health Policy: Pharmacovigilance includes Prescription Audit inclusive of
Antibiotic usage, Ministry of Health & Family Welfare, Government of India.

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sdsds

137
 UNIT - V

CHAPTER 01

Regulatory Concepts

Basic terminology

Guidance

Guidelines

Regulations

Orange Book

Federal Register

Code of federal regulatory

Purple book

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dfd

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 Regulatory Concepts
01 Basic terminology
Investigational product - New medicine developed by a manufacturer
Phase III clinical study-
Randomized study carried out by the manufacturer to assess the benefits and harms of an
investigational product
Active comparator (active treatment or active control) - Medically effective
treatment given as control condition in clinical studies
Placebo - Medically ineffectual treatment given as control condition in clinical studies
Three-arm study- Clinical study randomly allocating patients to one of the following
three conditions: (1) investigational product; (2) active comparator; (3) placebo
Two-arm head-to-head study (comparative trial)-
Clinical study randomly all ocating patients to one of the following two conditions:
(1) Investigational product;
(2) Active comparator
Superiority to placebo- Clinical study designed to demon strate that the difference in
terms of primary out come between the investigational product and placebo is statistically
significant in favor of the new medicine
Superiority to an active comparator - Clinical study designed to demonstrate that
the difference in terms of primary outcome between the investigational product and an active
comparator are statistically significant in favor of the new medicine
Non-inferiority to an active Comparator- Clinical study designed to demonstrate
that the efficacy of an investigational product is not clinically inferior to an active comparator
Efficacy in absolute terms- An investigational product supported by evidence of
superiority to placebo but not to an active comparator
Added value - An investigational product supported by evidence of superiority to an active
comparator.
Compulsory required
According to EMA guidelines, some study designs are necessary to prove the efficacy of an
investigational product for a given disorder, and therefore these studies must be conducted
to obtain a marketing authorization.
Recommended
According to EMA guidelines, some study designs are methodologically appropriate to prove
the efficacy of an investigational product for a given disorder, and therefore these studies
are recommended to obtain a marketing authorization, although EMA recognizes that there
may be alternative designs

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Acceptable
According to EMA guidelines, some study designs may be appropriate to prove the efficacy
of an investigational product for a given disorder, and therefore these studies may be
considered to obtain a marketing authorization, although EMA points out that there may be
better alternative designs.

Guidance, Guidelines, Regulations

Indian Regulations & Guidelines
C e n t r a l D r u g s St a n d a r d C o n t ro l O r g a n i z a t i o n
(CDSCO), Ministry of Health & Family Welfare, Govern-
CDSCO
ment of India provides general information about drug
regulatory requirements in India.

Drugs (Price Control) Order 1995 and other orders en-

forced by National Pharmaceutical Pricing Authority
NPPA
(NPPA), Government of India. View the list of drugs un-
der price control here…..

The Drugs & Cosmetics Act, 1940 regulates the import,

D & C Act, 1940
manufacture, distribution and sale of drugs in India.

Schedule M of the D&C Act specifies the general and

specific requirements for factory premises and materials,
Schedule M
plant and equipment and minimum recommended areas for
basic installation for certain categories of drugs.

Schedule T of the D&C Act prescribes GMP specifica-

Schedule T tions for manufacture of Ayurvedic, Siddha and Unani
medicines.

The clinical trials legislative requirements are guided by

Schedule Y
specifications of Schedule Y of the D&C Act.

The Ministry of Health, along with Drugs Controller

General of India (DCGI) and Indian Council for Medi-
GCP guidelines cal Research (ICMR)has come out with draft guidelines
for research in human subjects. These GCP guidelines are
essentially based on Declaration of Helsinki, WHO guide-
lines and ICH requirements for good clinical practice.

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The Pharmacy The Pharmacy Act, 1948 is meant to regulate the profes-
Act, 1948 sion of Pharmacy in India.

The Drugs and Magic The Drugs and Magic Remedies (Objectionable Adver-
Remedies (Objection- tisement) Act, 1954 provides to control the advertisements
able Advertisement) regarding drugs; it prohibits the advertising of remedies
Act, 1954 alleged to possess magic qualities.

The Narcotic Drugs The Narcotic Drugs and Psychotropic Substances Act,
and Psychotropic 1985 is an act concerned with control and regulation of
Substances Act, 1985 operations relating to Narcotic Drugs and Psychotropic
Substances.

Links to important international guidelines and regulatory bodies:

WHO guidelines on medicines policy, intellectual prop-

WHO (Medicines) erty rights, financing & supply management, quality &
safety, selection & rational use of medicines, technical co-
operation and traditional medicines.

WHO guidelines on all areas relevant to health of people

WHO sites
all over.

International Conference on Harmonization of Techni-

cal Requirements for the Registration of Pharmaceuti-
cals for Human Use (ICH) guidelines defining quality,
ICH safety, efficacy & related aspects for developing and reg-
istering new medicinal products in Europe, Japan and the
United States

Organization for Economic Collaboration and Devel-

OECD opment including 30 member countries covers economic
and social issues in areas of health care.

European Medicines Agency (EMEA), a decentralized body

of the European Union headquartered in London, prescribes
EMEA guidelines for inspections and general reporting and all as-
pects of human & veterinary medicines in the European Union.

Regulations, guidelines, notifications, news and commu-

US FDA
nications from US Food and Drug Administration.

139
 Specifications regulating medicines, medical devices,
TGA blood, tissues & chemicals, issued by Therapeutic Goods
Administration, the Australian regulatory body.

South Africa The department of Health, South Africa.

News, resources, documents and publications of the World

WTO Trade Organization (WTO), the global international or-
ganization dealing with the rules of trade between nations.

Collection of international food standards and guidelines

for processed, semi–processed and raw foods, adopted by
Codex Alimentarius
the Codex Alimentarius Commission under the Joint
FAO / WHO Food Standards Programme.

News, warnings, information and publications of Medicines

a n d H e a l t h c a re p ro d u c t s R e g u l a t o r y A g e n c y
MHRA
(MHRA), responsible for ensuring efficacy and safety of
medicines and medical devices in the UK.

Advisories, warnings, recalls, reports, publications, activi-

ties, legislations and guidelines from Health Canada, the
Health Canada
Federal Department responsible for health-related issues
in Canada.

Thai Food and Drug Administration laws and regulations

Thai FDA
with respect to drugs, food, cosmetics and narcotics.

Health Sciences Authority (HSA), the regulatory body of

HSA, Singapore
Singapore.

DOH, Philippines The Department of Health, Philippines.

Medsafe, New Zealand Medsafe, New Zealand Medicines and Medical Devices
Safety Authority.

140
 Regulatory information, news and publications of National
NPCB, Malaysia
Pharmaceutical Control Bureau, Malaysia.

Guidelines and useful information to ensure safety,

DGMP, Belgium efficacy and quality of medicines, issued
by Directorate-General Medicinal Products, Belgium.

Licensing and registration guidelines for medicinal prod-

BfArM, Germany ucts laid down by Federal Institute for Drugs and Medi-
cal Devices, Germany

SwissMedic Swiss regulatory agency for therapeutic products.

Regulatory and surveillance guidelines issued by

MPA, Sweden
Medical Products Agency, Sweden.

News, regulations and guidelines issued by The National

NAFDAC, Nigeria a g e n c y f o r F o o d A d m i n i s t r a t i o n a n d C o n t ro l
(NAFDAC), Nigeria.

Law and Acts

Background
Various laws and ethics govern pharmacy operations. While the laws are the legal
framework within which a pharmacy and its personnel can operate, ethics are professional
regulations, which govern a pharmacist in operating a pharmacy
Laws related to Community Pharmacy
1. The Drugs and Cosmetics Act, 1940 and Rules, 1945
2. The Narcotic Drugs and Psychotropic Substances Act and Rules, 1985.
3. Drugs Price Control Order, 1995
4. Consumer Protection Act, 1986
5. Infant Milk Substitutes, Feeding Bottles and Infant Foods Act, 1992
6. Drugs and Magic Remedies Act and Rules, 1954.
7. Prevention of Food and Adulteration Act, 1954.

141
The Drugs and Cosmetics Act, 1940, and Rules, 1945
The Drugs and Cosmetic Act, 1940, was enacted to regulate the import, manufacture,
sale and distribution of drugs and cosmetics. The Act includes laws governing the setting up
and operation of a pharmacy.
The emphasis of the Act is on self-regulation, but it can also be an effective too lint he
hands of the regulatory agencies for quality management through licensing, periodic
inspections to assess the extent of compliance, and initiating steps to continuously enhance
the degree of compliance.
The Act intends to:
1. Prevent manufacture and distribution of sub standard drugs.
2. Control the manufacture, sale and distribution of drugs and ensure standard and quality
drugs.
3. Monitor the licenses of premises from which medicines are sold/distributed.
4. Bring cosmetics in its purview, to regulate their import, manufacture, distribution and
sale.
Narcotic Drugs and Psychotropic Substances Act and Rules,1985
1. To consolidate and amend the law relating to narcotic drugs and psychotropic substances,
2. To make stringent provisions for the control and regulation of operations relating to
narcotic drugs and psychotropic substances,
3. To provide for the for feature of property derived from, or use din, illicit traffic in
narcotic drugs and psychotropic substances,
4. To implement the provisions of the International Convention on narcotic drugs and
psychotropic substances, and formatters connected there with.
Drugs (Prices Control) Order, 1995
The Drugs Prices Control Order,1995, is an order that lays down rules with respect to
the fixation of prices of bulk drug sand formulations.
The Order covers details like
1. Fixation of maximum sales prices of bulk drugs
2. Calculation of retail price of formulations
3. Fixation of retail price and ceiling price of scheduled formulations
4. Maintenance of records
5. Penalties for contravention of provision of the Order
6. Other details
The Drugs Price Control Order controls the prices of medicines, trying to make them
available at fair prices.
The Consumer Protection Act,1986
The Consumer Protection Act,1986, is a milestone in the history of the socio-economic
legislation in the country. It is one of the most progressive and comprehensive pieces of
legislation enacted for the protection of consumers.
1. The main objective of the Act is to provide better protection of the consumers.
142
2. The Act intends to provide simple, speedy and extensive redress of the consumer’s
grievances.
3. The Act enshrines certain rights of the consumers and provides for the setting up of
Consumer Protection Councils in the Centre and the states. The objective of these
Consumer Protection Councils will be to promote and protect the rights of the
consumers.
The salient features of the Act are summed up as under:
4. The Act applies to all goods and services unless specifically exempted by the Central
Government.
5. Since a pharmacy provides goods and services, it is also covered under this Act.
6. It covers all the sectors whether private, public or cooperative. The provisions of the
Act are compensatory in nature.
7. It enshrines the following rights of the consumers:
i. The right to be protected against the marketing of goods, which are hazardous to life
and property.
ii. The right to be informed about the quality, quantity, potency, purity, standard and price
of goods so as to protect the consumer against unfair trade practices.
iii. The right to be assured, wherever possible, access to a variety of goods at competitive
prices
iv. The right to be heard and to be assured that the consumer’s interests will receive due
consideration at appropriate forums.
v. The right to seek redress against unfair trade practices or unscrupulous exploitation of
consumers, and
vi. The right to consumer education.
The Infant Milk Substitutes, Feeding Bottles and Infant Foods (Regulation
of Production, Supply and Distribution) Act, 1992
This Act provides for the regulation of production, supply and distribution of infant
milk substitutes, feeding bottle sand infant foods with a view to protect and promote breast
feeding and ensure the proper use of infant foods. Under this Act, “Health care system”
means an institution or organization engaged, either directly or indirectly, in health care for
mothers, infants or pregnant women, and includes health workers in private practice, in a
pharmacy, in a drugstore and any association of health workers
According to this Act, no pharmacy should: -
1. Advertise, or take part in the publication of any advertisement, for the distribution,
sale or supply of infant milk substitutes, infant foods or feeding bottles.
2. Give an impression or create a belief in any manner that feeding of infant milk substitute
sand infant foods are equivalent to, or better than, mother’s milk.
3. Take part in the promotion of infant milk substitutes, infant foods or feeding bottles.
4. Supply or distribute samples of infant milk substitutes or feeding bottles or infant food
gifts of utensils or other articles.
5. Offer inducement of any other kind.

143
6. Use any health care system for displaying placards or posters relating to, or for the
distribution of, materials for the purpose of promoting the use or sale of infant milk
substitutes, infant foods or feeding bottles.
7. Demonstrate feeding with infant milk substitutes or infant foods to a mother of an
infant or to any member of her family, except through a health worker. The health
worker must clearly explain to the mother or to another member, the hazards of improper
use of infant milk substitutes, infant foods or feeding bottles.
8. Fix the remuneration of any employee or give any commission to such employee on the
basis of the volume of sale of such substitutes or bottles made by such employees.
9. Sell or otherwise distribute any infant milk substitute, infant foods and feeding bottles
unless they con form prescribed standards.
The Drugs and Magic Remedies (objectionable Advertisements) Act, 1954
This Act is enacted with a view to prevent objectionable and misleading advertisements
in order to discourage self-medication and self-treatment, especially with regard to certain
diseases of serious nature listed in the Act that can have a deleterious effect on the health of
the community, and may affect the well being of the people.
The Drugs and Magic Remedies Act prohibits a person, from taking part in the
publication of any advertisement referring to any drug which suggests the use of the drug
for:
a) Procurement of miscarriage of women, or prevention of conception in women.
b) Maintenance or improvement of the capacity of human beings for sexual pleasure.
c) The correction of menstrual disorder in women.
d) The diagnosis, cure, mitigation, treatment or prevention of any venereal disease.
This Act prohibits directly or indirectly giving a false impression regarding the true
character of the drug, making a false claim for it, or conveying any false or misleading
information about it.
Prevention of Food and Adulteration Act 1954
The Act makes provision for the prevention of adulteration of food.
The Prevention of Food and Adulteration Act is a social welfare legislation enacted to
curb the widely spread evil of adulteration of food product send angering national health
and human life.
The Act covers details including
❖ General provisions as to food.
❖ Analysis of food.
❖ Public analysts and inspectors
❖ Packing and labeling of foods
❖ Prohibition and regulation of sales
❖ Additives present
❖ Other details
❖ Definition

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- It is the publication of “Approved Drug Products with Therapeutic Equivalence
Evaluations” by the Food and Drug Administration.
- It is prepared by The Orange Book Staff, Center for Drug Evaluation and Research.
- It identified drug products on the basis of safety and effectiveness by the Food and
Drug Administration under the Federal Food, Drug, and Cosmetics Act.
- Drugs marketed only on the basis of safety or pre-1938drugs.
- The list is independent of any current regulatory action against a drug product.
- The main criterion for the inclusion of any product is that the product is the subject of
an application with an effective approval that has not been withdrawn for safety or
efficacy reasons.
- The FDA does not recommend substituting drugs that have not been determined to be
bioequivalent.
- Drugs that are not listed as bioequivalent should not be substituted for each other.

YEAR ACTION
May 31, 1978 The Commissioner of the Food and Drug Administration sent a letter
to officials of each state stating FDA’s intent to provide a list of all
prescription drug products that are approved by FDA for safety and
effectiveness, along with therapeuticequivalence determinations for
multisource prescription products.
January, 1979 The list was distributed (included only currently marketed prescription
drug products approved by FDA through NDAs and ANDAs under the
provisions of section505 of the Act)
October 31, 1980 The final rule (includes FDA’s response to the public comments on the
proposal) was published in the Federal Register (45 FR 72582).The
list incorporated appropriate corrections and additions.
Objectives
- To allow review of patterns of access and usage
- To allow discovery of use of unusual privileges
- To allow discovery of repeated attempts to bypass protections
- To serve as a deterrent by its existence
- To supply an additional form of user assurance

Orange Book
Background
It is the publication of “Approved Drug Products with Therapeutic Equivalence
Evaluations” by the Food and Drug Administration. It is prepared by The Orange Book Staff,
Center for Drug Evaluation and Research. It identified drug products on the basis of safety
and effectiveness by the Food and Drug Administration under the Federal Food, Drug, and
Cosmetics Act. Drugs marketed only on the basis of safety or pre-1938 drugs. The list is
145
independent of any current regulatory action against a drug product.
The main criterion for the inclusion of any product is that the product is the subject of
an application with an effective approval that has not been withdrawn for safety or efficacy
reasons. The FDA does not recommend substituting drugs that have not been determined to
be bioequivalent. Drugs that are not listed as bioequivalent should not be substituted for
each other.
History
May 31, 1978, The Commissioner of the Food and Drug Administration sent a letter to
officials of each state stating FDA’s intent to provide a list of all prescription drug products
that are approved by FDA for safety and effectiveness, along with therapeutic equivalence
determinations for multisource prescription products January, 1979 The list was distributed
(included only currently marketed prescription drug products approved by FDA through NDAs
and ANDAs under the provisions of section 505 of the Act) October 31, 1980 The final rule
(includes FDA’s response to the public comments on the proposal) was published in the
Federal Register (45 FR 72582). The list incorporated appropriate corrections and additions.
Objectives
To allow review of patterns of access and usage. To allow discovery of use of unusual
privileges To allow discovery of repeated attempts to bypass protections To serve as a
deterrent by its existence To supply an additional form of user assurance
Content of orange book
1.INTRODUCTION
1.1. Content and Exclusion
❖ Approved OTC drug products for those which are not marketed
❖ Approved prescription drug with therapeutic equivalence evaluations
❖ Drug products with Biologics Evaluation and Research
❖ List of approved products that have been discontinued from marketing
1.2. Therapeutic Equivalence-Related Terms
❖ Pharmaceutical equivalents
Contain the same active ingredient(s),
Have the same dosage form and route of administration, and
Identical in strength or concentration
May differ in shape, release mechanisms, and packaging
❖ Pharmaceutical alternatives
Contain the same therapeutic moiety but might differ in,
Salts, esters, or complexes form of the same moiety,
Different dosage forms,
Different strengths
❖ Therapeutic equivalents
❖ Therapeutic equivalents are expected to have the same clinical effect and safety profile.

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❖ Drug products are considered therapeutic equivalents if they are all of the following
Pharmaceutical equivalents
Bioequivalent
Approved as safe and effective
Adequately labeled
Manufactured in compliance with current Good Manufacturing Practice regulations
❖ Bioequivalence and bio-availability
❖ Drug products are considered bioequivalent if they are pharmaceutical equivalents
whose rate and extent of absorption are not statistically different when administered to
subjects at the same molar dose under similar experimental conditions
❖ Bioequivalence use to determine Therapeutic Equivalents
1.3. Statistical Criteria for Bioequivalence
❖ In short Bioequivalence refers to equivalent release of the same drug substance from
two or more drug products.
❖ The standard bioequivalence (PK) study is conducted in 24-36 adults using a two-
treatment crossover study design.
❖ Alternately, a four-period, replicate design crossover study can also be used.
❖ The statistical methodology for analyzing these bioequivalence studies is called the
two one-sided test procedure.
❖ Two situations are tested with this statistical methodology
❖ Pharmacokinetic parameters determine are AUC and Cmax.
❖ Two criteria include,
i. Whether a generic product(test), when substituted for a brand-name product
(reference) is significantly less bio-available. (A limit of test-product average/
reference-product average of 80%)
ii. Whether a brand-name product when substituted for a generic product is significantly
less bio-available. (A limit of reference-product average/test-product average125%)
❖ A difference of greater than 20% for each of the above tests was determined to be
significant
❖ The confidence interval for both pharmacokinetic parameters, AUC and Cmax, must
be entirely within the 80% to 125% boundaries cited above.
1.4. Reference Listed Drug
❖ A reference listed drug means the listed drug identified by FDA as the drug product
upon which an applicant relies in seeking approval of its ANDA.
❖ The aim of FDA is to avoid possible significant variations among generic drugs and
their brand name counterpart.
❖ The reference listed drug is identified by the symbol “+” in the Prescription and Over-
the-Counter (OTC) Drug Product Lists.
❖ List is available for oral dosage forms, injectables, ophthalmic, otics, and topical products.

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1.5. General Policies and Legal Status
❖ The List contains public information and advice.
❖ It is not compulsory the drug products which may be purchased, prescribed, dispensed,
or substituted for one another, nor does it, should be avoided.
❖ Exclusion of a drug product from the List does not necessarily mean that the drug
product is not safe or effective, or that such a product is not therapeutically equivalent
to other drug products.
❖ Rather, FDA has not evaluated the safety, effectiveness, and quality of the drug product.
1.6. Practitioner/User Responsibilities
❖ Professional care and judgment should be exercised in using the list.
❖ Practitioner should be aware of the multi-source and single-source drug products.
i. Multisource Drug Product means those pharmaceutical equivalents available from
more than one manufacturer. For such products, a therapeutic equivalence (TE) code
is included and, in addition, product information is highlighted in bold face and
underlined.
ii. Single-Source Drug Product means only one approved product is available for
particular active ingredient, dosage form, route of administration, and strength. For
such product no therapeutic equivalence code is included.
❖ Products on the List are identified by the names of the holders of approved applications
(applicants) who may not necessarily be the manufacturer of the product:
❖ Applicants like Manufacture, Contract Manufacturer, Repackager, Distributor or
Marketer.
1.7. Therapeutic Equivalence Evaluations Codes
❖ The coding system for therapeutic equivalence evaluations
First letter: therapeutically equivalent to other pharmaceutically equivalent products
Second letter: provide additional information on the basis of FDA’s evaluations
1.8. Description of Special Situations
Example
Drugs Description of Special Situations
Amino-acid and Protein These products differ in the amount and kinds of amino-acids
Hydrolysate injections they contain, and therefore, are not considered pharmaceutical
equivalents. For this reason, these products are not considered
therapeutically equivalent.
1.9. Therapeutic Equivalence Code Change for a Drug Entity
❖ Such changes occur in response to a petition or on its own initiative.
❖ Changes will generally occur when new scientific information affects the therapeutic
equivalence of an entire category of drug products in the List.
1.10. Discontinued Section
❖ When the product has been discontinued from marketing,

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❖ Are for military use,
❖ Or have had their approvals withdrawn for other than safety or efficacy reasons
❖ Drug Products for exportation
2.1. Key Sections for Using the Drug Product Lists
❖ This contains illustrations, along with Drug Product Lists, indices, and lists of
abbreviations and terms which facilitate their use.
i. Illustration: Depicts the format found in the Prescription Drug Product List.
ii. Drug Product Lists: The Prescription and OTC drug product lists, arranged
alphabetically by active ingredient (s), contains product identification information
(active ingredients, dosage forms, routes of administration, product names,
application holders, strengths) for single and multiple ingredient drug products.
Also shown are the application number and drug product number.
iii. Product Name Index.
iv. Product Name Index Listed by Applicant.
v. Uniform terms.
2.2. Drug Product Illustration
❖ Active ingredient
❖ Dosage form: route of administration
❖ Trade or generic name
❖ Applicant
❖ Available strength of product
❖ Applicant number & product number
❖ Product number is for fda internal computer data use only
2.3. Therapeutic Equivalence Evaluations Illustration
❖ Drug Product reviewed
❖ It includes only full approval products and not tentative approval products
❖ Drug Product of Repackager/Distributor is considered to be therapeutically equivalent
to the Application Holder’s product
❖ The new approvals and required changes in data are included in each subsequent edition.
Even monthly cumulative supplements are published

Federal Register
Background
Published by the Office of the Federal Register, National Archives and Records
Administration (NARA), the Federal Register is the official daily publication for rules,
proposed rules, and notices of Federal agencies and organizations, as well as executive orders
and other presidential documents.

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Federal Register
The Federal Register is the official journal of the federal government of the United
States that contains government agency rules, proposed rules, and public notices. It is
published every weekday, except on federal holidays.
The final rules promulgated by a federal agency and published in the Federal Register are
ultimately reorganized by topic or subject matter and codified in the Code of Federal
Regulations (CFR), which is updated annually.
The Federal Register is compiled by the Office of the Federal Register (within
the National Archives and Records Administration) and is printed by the Government
Publishing Office. There are no copyright restrictions on the Federal Register; as a work of
the U.S. government, it is in the public domain
History
The Federal Register system of publication was created on July 26, 1935, under
the Federal Register Act. The first issue of the Federal Register was published on March 16,
1936. [14] In 1946 the Administrative Procedure Act required agencies to publish more
information related to their rulemaking documents in the Federal Register.
On March 11, 2014, Rep. Darrell Issa introduced the Federal Register Modernization
Act (H.R. 4195), a bill that would require the Federal Register to be published (e.g., by
electronic means), rather than printed, and that documents in the Federal Register be made
available for sale or distribution to the public in published form. The American Association
of Law Libraries (AALL) strongly opposed the bill, arguing that the bill undermines citizens’
right to be informed by making it more difficult for citizens to find their government’s
regulations. According to AALL, a survey they conducted “revealed that members of the
public, librarians, researchers, students, attorneys, and small business owners continue to
rely on the print” version of the Federal Register. AALL also argued that the lack of print
versions of the Federal Register and CFR would mean the 15 percent of Americans who don’t
use the Internet would lose their access to that material. The House voted on July 14, 2014,
to pass the bill 386–0.
Contents
The Federal Register provides a means for the government to announce to the public
changes to government requirements, policies, and guidance.
❖ Proposed new rules and regulations
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❖ Both proposed and final government rules are published in the Federal Register.
A Notice of Proposed Rulemaking (or “NPRM”) typically requests public comment on
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and the text of a final rule along with a discussion of the comments is published in
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contact information for people and organizations interested in making comments to
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 the agencies and the agencies are required to address these concerns when it publishes
its final rule on the subject.
❖ The notice and comment process, as outlined in the Administrative Procedure Act,
gives the people a chance to participate in agency rulemaking. Publication of documents
in the Federal Register also constitutes constructive notice, and its contents
are judicially noticed.
❖ The United States Government Manual is published as a special edition of the Federal
Register. Its focus is on programs and activities.
Format
Each daily issue of the printed Federal Register is organized into four categories:
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federal agencies)
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❖ Notices (such as scheduled hearings and meetings open to the public and grant
applications)
Citations from the Federal Register are [volume] FR [page number] ([date]), e.g., 71
FR 24924 (Apr. 7, 2006).
The final rules promulgated by a federal agency and published in the Federal Register are
ultimately reorganized by topic or subject matter and re-published (or “codified”) in the Code
of Federal Regulations (CFR), which is updated annually.
Availability
Copies of the Federal Register may be obtained from the U.S. Government Publishing
Office. Most law libraries associated with an American Bar Association–accredited law
school will also have a set, as will federal depository libraries.
Free sources
The Federal Register has been available online since 1994. Federal depository
libraries within the U.S. also receive copies of the text, either in paper or microfiche format.
Outside the U.S., some major libraries may also carry the Federal Register.
As part of the Federal E-Government eRulemaking Initiative, the web
site Regulations.gov was established in 2003 to enable easy public access to agency dockets
on rulemaking projects including the published Federal Register document. The public can
use Regulations.gov to access entire rulemaking dockets from participating Federal agencies
to include providing on-line comments directly to those responsible for drafting the
rulemakings. To help federal agencies manage their dockets, the Federal Docket Management
System (FDMS) was launched in 2005 and is the agency side of regulations.gov.
In April 2009, Citation Technologies created a free, searchable website for Federal
Register articles dating from 1996 to the present.
GovPulse.us, a finalist in the Sunlight Foundation’s Apps for America 2,provides a
web 2.0 interface to the Federal Register, including spark lines of agency activity and maps
of current rules.
On July 25, 2010, the Federal Register 2.0 website went live. The new website is a
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collaboration between the developers who created GovPulse.us, the Government Publishing
Office and the National Archives and Records Administration.
On August 1, 2011, the Federal Register announced a new application programming
interface (API) to facilitate programmatic access to the Federal Register content. The API is
f u l l y R E S T f u l , u t i l i z i n g t h e H AT E O A S a r c h i t e c t u r e w i t h r e s u l t s d e l i v e r e d i n
the JSON format. Details are available at the developers page and Ruby and Python client
libraries are available.
Paid sources
In addition to purchasing printed copies or subscriptions, the contents of the Federal
Register can be acquired via several commercial databases:
❖ Citation Technologies offers the complete Federal Register and Code of Federal
Regulations (CFRs) through subscription-based web portals such as CyberRegs. [12]
❖ HeinOnline (1936): Full coverage available dating back to 1936 in an image-based
searchable PDF format.
❖ LexisNexis (July 1, 1980): Searchable text format since 45 FR 44251.
❖ Westlaw (January 1, 1981): Searchable text format since 46 FR 1. The Unified Agenda
and the official English text of the 1980 United Nations Convention on Contracts for
the International Sale of Goods, which became effective January 1, 1988, are included.
Sunshine Act Meeting Notices are not available prior to 1991. Unified Agenda
documents are not available prior to October 1989.
Volumes of Federal Register
Volumes 60 (1995) to present
Available for download as an entire issue (in PDF and XML formats) or as smaller
sections (in PDF and text formats).
View the Table of Contents for the most recent issue or for previous issues by clicking
the TOC button for specific issues in browse. Sign up for a free email subscription of the
daily Table of Contents.
XML files can be downloaded in bulk as a zip file by the year (volume) or month in
the Bulk Data Repository. Information on the legal status, authenticity, and schema of the
Federal Register XML renditions can be found in the User Guide Document - Federal Register
XML Rendition.
Volumes 59 (1994) and older are digitized versions of historical issues of the Federal
Register being made available as full issue PDF only. Note: Volume 59 (1994) has entire
issues available in PDF format only, and smaller sections available in text format only. These
digitized volumes include all issues and parts of the official printed edition. (See below for
more information on searching the Digitized Federal Register.)
❖ Volume 59 (1994) issues are a special case. They originally existed in the system in
text format only, but now also have PDF format available for the entire issue. Smaller
sections are available only in text format.
The Federal Register Index and List of CFR Sections Affected (LSA)
Gov info provides a tool to easily find CFR Parts Affected from the Federal
Register. Learn more about this tool below.

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 To find a more recent, unofficial issue of the Federal Register, view the Public
Inspection issue online at www.federalregister.gov, a service of the National Archives
and Records Administration’s Office of the Federal Register.
You may be able to find new rules and regulations on an agency’s website before it is
published in the Federal Register, but this is not considered the official version and the
effective date is generally based on when it is published in the Federal Register.
❖ GPO’s Online Bookstore has the following available for purchase:
Individual issues in print and microfiche
Annual subscription in print and microfiche
Federal Register Index in print and microfiche
Organization of federal register
Table of Contents and Preliminary Pages
This section of the Federal Register contains a comprehensive alphabetical listing by
agency name of all documents in the issue. Under each agency, the documents are arranged
by classification—Rules, Proposed Rules, or Notices. Each entry includes the page number
where the document begins and a brief description of the document.
If Presidential Documents appear in the Federal Register they are listed in alphabetical
order in the Contents under the heading “Presidential Documents”. Appearing at the end of
the Contents is a list of separate parts published in the issue, if applicable. The documents
appearing in the separate part are also listed under the agency in the table of contents.
Also appearing in the preliminary pages (Contents Section) of each day’s Federal
Register is a list of the CFR Parts Affected in This Issue. Under each CFR title the parts
affected by the rules and proposed rules in the issue are listed along with the page numbers
where relevant documents begin.
The Reader Aids section of the Federal Register is designed to help the reader find
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in the preliminary pages (Contents section) which are more oriented to one particular issue
of the Federal Register.
Rules and Regulations Section
This section of the Federal Register contains final rules and regulations: regulatory
documents having general applicability and legal effect. Most rules are keyed to and codified
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changes to the CFR and state the effective date for any change.
Each document begins with a heading that includes the name of the issuing agency
(and sub-agency if appropriate), the CFR title and part(s) affected, and a brief description of
the specific subject of the document. In some cases, an agency includes a docket number,
which identifies the document within the agency’s internal filing system. A Regulation
Identifier Number (RIN) may also be included.
This section also contains interim rules that are issued without prior notice and are
effective immediately; the interim rule is designed to respond to an emergency situation and
is usually followed by a final rule document which confirms that the interim rule is final,
addresses comments received, and includes any further amendments. Additionally, this section

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includes documents that have no regulatory text and do not amend the CFR, but either affects
the agency’s handling of its regulations or are of continuing interest to the public in dealing
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codified language.
The terms “rules” and “regulations” have the same meaning within the Federal Register
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Proposed Rules Section
This section of the Federal Register contains notices to the public of the proposed
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Many proposed rules are documents that suggest changes to agency regulations in the
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This section also contains documents relating to previously published proposed rules,
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This section includes advanced notices of proposed rulemaking, which describe a
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response concerning the necessity for regulation and the adequacy of the agency’s anticipated
regulatory action. Additionally, many agencies voluntarily publish proposed changes to
procedural rules, interpretative rules and agency policies to gather public comments.
Each document begins with a heading that includes the name of the issuing agency
(and sub-agency if appropriate), the CFR title and part(s) affected, and a brief description of
the specific subject of the document. In some cases, an agency docket number, which identifies
the document within the agency’s internal filing system. A Regulation Identifier Number
(RIN) may also be included. Instructions for filing comments and the date by which comments
must be filed are provided.
The terms “rules” and “regulations” have the same meaning within the Federal Register
publication system.
Notices Section
This section of the Federal Register contains documents other than rules or proposed
rules that are applicable to the public. Notices of hearings and investigations, committee
meetings, agency decisions and rulings, delegations of authority, issuances or revocation of
licenses, grant application deadlines, availability of environmental impact statements, filing
of petitions and applications, and agency statements of organization and functions are
examples of documents appearing in this section.
Presidential Documents Section
This section of the Federal Register contains documents signed by the President and
submitted to the Office of the Federal Register for publication. Presidential documents include
Proclamations and Executive Orders, as well as other documents such as determinations,
letters, memorandums, and reorganization plans. The documents are compiled annually in
title 3 of the Code of Federal Regulations (CFR).

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Sunshine Act Meetings
This section of the Federal Register contains notices of meetings published under the
“Government in the Sunshine Act” (Pub. L. 94-409) 5 U.S.C. 552b(e)(3).
In recognition of the public’s right to the fullest possible information about the Federal
decision-making process, the Government in the Sunshine Act requires that meetings of
Government agencies be open to the public, with certain specified exceptions. The Act also
requires that public announcement be made in the Federal Register of the time, place, and
subject matter of the meeting, the name and telephone number of the agency official to
contact for more information, and whether the meeting is open or closed to the public.
Reader Aids
This section of the Federal Register is designed to help the reader find specific
information in the Federal Register system, as distinguished from the finding aids in the
preliminary pages (Contents section) which are more oriented to one particular issue of the
Federal Register.
❖ Information and Assistance. Appearing first is the listing of Office of the Federal
Register telephone numbers to call for specific information.
❖ Federal Register Pages and Dates. This is a table of the inclusive page numbers and
corresponding dates for the current month’s Federal Register.
❖ CFR Parts Affected During the Current Month. This is a cumulative list of Code of
Federal Regulations (CFR) parts affected by rules and proposed rules published in the
Federal Register during the current month.
Corrections Section
This section of the Federal Register contains editorial corrections of previously
published Presidential, Rule, Proposed Rule, and Notice documents. These corrections are
prepared by the Office of the Federal Register to correct typographical or clerical errors
made in the printing of the Federal Register. Agency prepared corrections are issued as signed
documents and appear in the appropriate document categories elsewhere in the issue.
CFR Parts Affected from the Federal Register
The Federal Register contains rules and regulations which are regulatory documents
having general applicability and legal effect. Most rules are codified in the Code of Federal
Regulations (CFR).
Browse CFR Parts Affected from the Federal Register to find final and proposed rules
that affect the CFR and have been published in the Federal Register within the past 24 hours,
week, month, or within a specific date range.
CFR Parts Affected is also contained in the Reader Aids section of each Federal Register
issue.
Unified Agenda
The Unified Agenda, as published in the Federal Register, is available on a separate
page on govinfo. The complete Unified Agenda is available to the public at Reginfo.gov.
The Unified Agenda of Federal Regulatory and Deregulatory Actions (Unified Agenda)
provides uniform reporting on the actions administrative agencies plan to issue in the near
and long term. Executive Order 12866 “Regulatory Planning and Review,” signed September
30, 1993 (58 FR 51735), and Office of Management and Budget memoranda implementing
section 4 of that Order establish minimum standards for agencies’ agendas, including specific

155
types of information for each entry. Each edition of the Unified Agenda includes regulatory
agendas from Federal entities that currently have regulations under development or review.
Agencies of the United States Congress are not included. Fall editions of the Unified Agenda
include The Regulatory Plan, which presents agency statements of regulatory priorities and
additional information about the most significant regulatory activities planned for the coming
year.
All editions of the Unified Agenda through the spring 2007 edition were published in
their entirety in the Federal Register. Beginning with the fall 2007 edition, the Agenda
published in the Federal Register is limited, in general, to agency regulatory flexibility
agendas and The Regulatory Plan. Agency regulatory flexibility agendas, which are required
by the Regulatory Flexibility Act (PDF) to be published in the Federal Register, include
only those rules that may have a significant economic impact on a substantial number of
small entities and entries that have been selected for periodic review under section 610
(PDF) of the Regulatory Flexibility Act.
The Unified Agenda is compiled by the Regulatory Information Service Center, a
component of the U.S. General Services Administration, in cooperation with the Office of
Management and Budget’s Office of Information and Regulatory Affairs. Applicable agendas
are then published by the Office of the Federal Register, National Archives and Records
Administration (NARA) in the Federal Register. The Regulatory Information Service Center
assigns a Regulation Identifier Number (RIN) to identify each regulatory action listed in the
Unified Agenda.

Code of federal regulatory

Background
The Code of Federal Regulations (CFR) annual edition is the codification of the general
and permanent rules published in the Federal Register by the departments and agencies of
the Federal Government.
The online CFR is a joint project authorized by the publisher, the National Archives
and Records Administration’s (NARA) Office of the Federal Register (OFR), and the
Government Publishing Office (GPO) to provide the public with enhanced access to
Government information.
Note: In the official paper bound version and the official PDF versions of 2007 edition
of Title 49 volume 6 parts 400-599, the header incorrectly reads “(10-1-06 Edition)” and
should have read “(10-1-07 Edition)”.
The CFR on govinfo is current with the published print version of the CFR. When the
print editions are released, the online version is also made available. If a CFR Title or volume
is not listed in the CFR browse, that volume has not yet been published.
The 50 subject matter titles contain one or more individual volumes, which are updated
once each calendar year, on a staggered basis. The annual update cycle is as follows:
Titles 1-16 are revised as of January 1
Titles 17-27 are revised as of April 1
Titles 28-41 are revised as of July 1

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 Titles 42-50 are revised as of October 1
govinfo currently contains titles from 1996 to the present. CFR volumes are
added concurrent with the release of the paper editions. When revised CFR volumes are
added, the prior editions remain on govinfo as a historical set. Bulk data downloads of
Code of Federal Regulations XML files are available to the general public
via Data.gov and GPO’s Bulk Data Repository. Information on the legal status, authenticity,
and schema of the Code of Federal Regulations XML renditions can be found in the User
Guide Document - Code of Federal Register XML Rendition. To see more recently
updated titles of the CFR, visit the electronic Code of Federal Regulations (e-CFR), a
regularly updated, unofficial editorial compilation of CFR material and Federal Register
amendments. The eCFR is updated on a daily basis. To see a cumulative list of CFR sections
that have been changed at any time since each CFR title was last updated, view the List of
CFR Sections Affected (LSA).To find final and proposed rules that affect the CFR and
have been published in the Federal Register within the past 24 hours, week, month, or within
a specific date range, browse the CFR Parts Affected from the Federal Register
Organization
The CFR is divided into 50 titles that represent broad areas subject to Federal regulation.
Each title is divided into chapters, which usually bear the name of the issuing agency. Each
chapter is further subdivided into parts that cover specific regulatory areas. Large parts may
be subdivided into subparts. All parts are organized in sections, and most citations to the
CFR refer to material at the section level.
Structure of a CFR citation
The following describes how information is contained in a CFR citation.
❖ Title: The numeric value to the left of “CFR”
❖ Part: The numeric value to the right of “CFR” and preceding the period (“.”)
❖ Section/Subpart: The numeric value to the right of the period (“.”) A subpart is a
letter of the alphabet (A-Z) that is used to retrieve an entire subpart of the CFR rather
than many individual sections. For example: Subpart E.
❖ Revision Year: Four-digit year from the “Revised as of” text represents the year being
cited. The revision year is not always available when the CFR is cited.
❖ Example: 21 CFR 310.502 Revised as of April 1, 1997
❖ Title: 21
❖ Part: 310
❖ Section: 502
❖ Year: 1997
Parallel Table of Authorities and Rules for the Code of Federal Regulations
and the United States Code
The Parallel Table of Authorities and Rules lists rulemaking authority (except 5 U.S.C.
301) for regulations codified in the Code of Federal Regulations. Also included are statutory
citations which are noted as being interpreted or applied by those regulations.

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 The table is divided into four segments and within each segment the citations are
arranged in numerical order:
1. For the United States Code citations, by title and section;
2. For the United States Statutes at Large citations, by volume and page number;
3. For public laws citations, by number;
4. For Presidential documents (Proclamations, Executive orders, and Reorganization plans)
citations, by document number. Entries in the table are taken directly from the
rulemaking authority citation provided by Federal agencies in their regulations. Federal
agencies are responsible for keeping these citations current and accurate. Because
Federal agencies sometimes present these citations in an inconsistent manner, the table
cannot be considered all-inclusive. The portion of the table listing the United States
Code citations is the most comprehensive, as these citations are entered into the table
whenever they are given in the authority citations provided by the agencies. United
States Statutes at Large and public law citations are carried in the table only when
there are no corresponding United States Code citations given. Beginning in 2017, the
table is available in volumes of the CFR Index and Finding Aids publication on govinfo.
You can download the entire CFR Index and Finding Aids volume or just the Parallel
Table of Authorities and Rules.
Searching the Code of Federal Regulations
You can find and search the Code of Federal Regulations by:
❖ Using Basic Search for keyword and metadata fielded searches,
❖ Using Advanced Search; fields specific to the CFR will display after you select Code
of Federal Regulations in the Refine by Collection column,
❖ Using Citation Search to retrieve a single Code of Federal Regulations document in
PDF format if you know the Volume and Page of the document,
❖ Refining search results by clicking on links in the Refine Your Search panel on the
left-hand side of the page (the sections under Refine Your Search correspond to the
metadata available for the documents), and
❖ Browsing the Code of Federal Regulations browse page.
❖ General govinfo Search Tips
❖ Search Examples
❖ Search by Citation- For example, 7 CFR 1951.7 from 2016.
❖ Using Basic Search, enter: collection: cfr and citation:”7 CFR 1951.7" and
publishdate:2016
❖ Using Advanced Search, select Code of Federal Regulations under Refine by Collection,
then under Search In select Citation in the first box and enter “7 CFR 1951.7” in the
second box
❖ Using Citation Search, select Code of Federal Regulations from Select Collection box,
select 2016 from Select Year box, select 7 from Select Title Number box, and
enter 1951.7 in Section box
❖ Search by Title Number- For example, CFR documents from Title 7.
❖ Using Basic Search, enter: collection: cfr and cfrtitlenum:7
158
❖ Using Advanced Search, select Code of Federal Regulations under Refine by Collection,
then under Search In select CFR Title Number in the first box and enter 7 in the second
box
❖ Search by Title and Part Number- CFR documents from Title 7, Part 1951.
❖ Using Basic Search, enter: collection: cfr and cfrtitlenum:7 and cfrpartnum:1951
❖ Using Advanced Search, select Code of Federal Regulations under Refine by Collection,
then under Search In select CFR Title Number in the first box, enter 7 in the second
box, click + Additional Criteria, select CFR Part Number from the resulting box, and
enter 1951 in the next box
❖ Search by Keyword- For example, Code of Federal Regulations documents with
“emissions” in the full text of the publication.
❖ Using Basic Search, enter: emissions and collection: cfr
❖ Using Advanced Search, select Code of Federal Regulations under Refine by Collection,
then under Search In enter emissions in the second box
❖ Sample Code of Federal Regulations URLs
❖ Govinfo uses two key pieces of information to construct predictable URLs to documents
and Details pages:
❖ Granule ID for the Code of Federal Regulations is used to identify the specific section,
part, subpart, chapter, or subchapter within a volume of the publication.
❖ Package ID is used to identify an individual volume of the publication.
Metadata Fields and Values
Metadata fields and values can be used to increase the relevancy of your searches. The
metadata fields available for the Code of Federal Regulations are listed in the table below.
Metadata fields and values are used throughout govinfo for
❖ Narrowing Your Search,
Identifier Structure/Metadata Field Examples

Granule ID Chapter CFR-2008-title39-vol1-chapI

CFR-{Year}-title {CFR Title CFR-2008-title39-vol1-chapI-
Number}-vol {CFR Volume subchap B
Number}-chap {Chapter CFR-2008-title39-vol1-part20
Identifier} CFR-2008-title39-vol1-part777-
Subchapter subpartA
CFR-{Year}-title {CFR Title CFR-2008-title39-vol1-sec20-2
Number}-vol {CFR Volume
Number}-chap {Chapter Identifier}-
sub chap {Subchapter Identifier}
Part
CFR-{Year}-title {CFR Title
Number}-vol {CFR Volume
Number}-part {Part Number}
Subpart
CFR-{Year}-title {CFR Title

159
 Number}-vol {CFR Volume
Number}-part {Part
Number}-subpart {Subpart
Identifier}Section
CFR-{Year}-title {CFR Title
Number}-vol {CFR Volume
Number}-sec {Part Number}-
{Section Identifier - only the
portion after the period in the cita-
tion}
Note: When a chapter, subchapter,
part, section, or subpart is split over
multiple volumes, combined files are
not available and direct links to docu-
ments must be accessed at a more
granular level.
Package ID CFR-{Year}-title {CFR Title CFR-2008-title39-vol1
Number}-vol {CFR Volume
Number}

❖ Browsing Government Publications,

❖ Field Operators,
❖ Advanced Search, and
❖ Display on Details Pages.
Metadata fields and values can be entered into the Basic Search box using field
operators. The field operators available for the Code of Federal Regulations are listed in the
table below, along with examples for each metadata field. Using Field Operators
Some of these metadata fields are made available for use in Advanced Search. The
metadata values can be entered in the same format for the fields available on the Advanced
Search Page. Using Advanced Search
Code of Federal Regulations Related Resources
❖ List of CFR Sections Affected - Proposed, new, and amended Federal regulations that
have been published in the Federal Register since the most recent revision date of a
CFR title.
❖ Browse CFR Parts Affected from the Federal Register - Final and proposed rules that

Metadata Field Metadata Field Field Operator Field Operator

Display Name Definition Example(s)
Collection The collection to which Collection collection: cfr
the document belongs. Note: “cfr” is used for
Typically, the same as the the Code of Federal
publication or series. Regulations

160
Metadata Field Metadata Field Field Operator Field Operator
Display Name Definition Example(s)
Government The names of the government government author:
Author Government organizations author: “office of the federal
responsible for authoring register”
or assembling the
document.
Publication Date The date the publish date: publish date:
document was first 2016-01-01Date format is
made available YYYY,
to the public. YYYY-MM, or
YYYY-MM-DD
Language The language code of the language: language
original document, from
the ISO639-2b standard.
Former Package The document ID mods: mods:
ID of the “package.” identifier:(@type:” identifier:(@type:”
former package former package
identifier”:” identifier”:”44CFR”)
________”)
SuDoc C l a s s The SuDoc class number sudocclass: sudocclass:”AE 2.106/
Number from the U.S. Superinten- 3:”Note: The SuDoc Class
dent of Documents which Numbers are at the class
classifies Government stem level, not the book
publications by publish- number level.
ing agency.
Ingestion Date The date the document ingest date: ingest date : 2009-12-29
was ingested into the Date format is
preservation repository. YYYY-MM-DD
Electronic The URL where the docu- url: url:pkg/CFR-2016-
Location (URL) ment or the document in title1-vol1/pdf/
context (the content de- CFR-2016-title1-
tail page) is located. vol1-sec1-1.pdf
Publisher The government organi- publisher: publisher: “Office of the
zation who publishes the Federal Register, National
document or publication. Archives and Records
Not typically the Govern- Administration”
ment Publishing Office
(who serves as the printer
and distributor), except in
the case of Congressional
publications.

161
Metadata Field Metadata Field Field Operator Field Operator
Display Name Definition Example(s)
Branch The branch of Govern- branch: branch: executiveNote:
ment responsible for the Possible Values: Executive,
document’s contents. Legislative, Judicial
Type of Resource The media type for the Type of resource: typeofresource:text
document, typically
“text”. Defined as part of
the Library of Congress
MODS standard.
WAIS Database The name of the WAIS waisdbname: waisdbname:2016_cfr_1v1
Name database to which the
document belonged in the
former GPO Access
system.
Record Origin How the record was record origin: record origin:
originally generated. “machine
Typically, generated”
“machine
generated.”
Title The title of the title: title: “agriculture”
publication.
CFR Title CFR Title Number, cfrtitlenum: cfrtitlenum:7
Number an integer number
from 1 to 50.
CFR Part CFR part number, an cfrpartnum: cfrpartnum:1951
Number integer number of the
part within the title.
CFR Section The CFR section cfrsectionnum: cfrsectionnum:94.1
Number number.
Heading Search for the heading. heading: heading: “part 2”
heading: “subpart I”
heading: “chapter 9”
CFR Subject The subject group for the cfr subject: cfr subject:”income tax”
Group sections, typically used
for very large parts, such
as the Internal Revenue
part on income taxes.
CFR Citation Citation references to cfr citation: cfrcitation:”40 CFR Part
the Code of 32"
Federal Regulations.

162
Metadata Field Metadata Field Field Operator Field Operator
Display Name Definition Example(s)
CFR Part cfrpartheading: cfrpartheading:”part 2"
Heading
CFR Part Title cfrparttitle: cfrparttitle:”capital
construction fund”
CFR SubPart cfrsubpartheading: cfrsubpartheading:”
Heading subpart b”
CFR SubPart cfrsubparttitle: cfrsubparttitle:”registration
Title of pilots”
CFR Chapter cfrchapterheading: cfrchapterheading:”
Heading chapter 2"
CFR Chapter cfrchaptertitle: cfrchaptertitle:”rural
Title housing service”
CFR Appendix cfrappheading: cfrappheading:”
Heading appendix a”
CFR Appendix cfrapptitle: cfrapptitle:”alternate
Title foods for meals”
Book Contents cfrbookcontents: cfrbookcontents:”
Statement parts 1 to 199"
CFR Authority cfrauthority: cfrauthority:”44 U.S.C.
Ch. 35"
CFR Source cfrsource: cfrsource:”38 FR 25170"
CFR Cross cfrxref: cfrxref:”42 CFR 110"
Reference
CFR Editorial cfreditorial: cfreditorial:”70 FR 57994"
Notes
CFR Citation cfrcitationtext: cfrcitationtext:”60
Text: FR 13895, Mar. 15, 1995,
as amended at 69
FR 42100, July 14, 2004"
Citation T h e G P O s t a n d a r d citation: citation:”9 CFR 2.2"
method for searching
citation references from
the selected publication.
Congressional C i t a t i o n r e f e r e n c e s t o billscitation: bills citation:”h.r. 1"
Bills Citation Congressional Bills.

163
Metadata Field Metadata Field Field Operator Field Operator
Display Name Definition Example(s)
Congressional C i t a t i o n r e f e r e n c e s t o crptcitation: crptcitation:”S.
Report Citation Congressional Reports. Rept. 99-296"
Public and C i t a t i o n r e f e r e n c e s t o plawcitation: plawcitation:”public
Private Law Public or Private Laws. law 71-126"
Citation
United States Citation references to the uscodecitation: uscodecitation:”42
Code Citation United States Code. U.S.C. 3121"
Statutes at Large C i t a t i o n r e f e r e n c e s t o statute citation: statutecitation:”70
Citation Statutes at Large. Stat. 1046"
Federal Register Reference to the Federal frcitation: frcitation:”52 FR 49386"
Citation Register, in standard
citation format.
Reference Cita- R e f e r e n c e t o a n o t h e r refcitation: refcitation:”42 U.S.C.
tion document within the text 3121"
of a document.

affect the CFR and have been published in the Federal Register within the past 24
hours, week, month, or within a specific date range.
❖ Electronic Code of Federal Regulations (e-CFR) - A regularly updated, unofficial
editorial compilation of CFR material and Federal Register amendments produced by
the National Archives and Records Administration’s Office of the Federal Register and
the Government Publishing Office
❖ Regulations.gov - Find, review, and submit comments on Federal rules that are open
for comment and published in the Federal Register. Managed by the U.S. Environmental
Protection Agency eRulemaking Program Management Office.
❖ A Guide to the Rulemaking Process (PDF) - Prepared by the Office of the Federal
Register, National Archives and Records Administration.
❖ Contact your local Federal Depository Library - Including issues prior to 1996 using
the Federal Depository Library Directory.
❖ Purchase individual CFR titles in print - From GPO’s Online Bookstore
❖ Download the CFR (Annual) in bulk XML - From GPO’s bulk data repository.
❖ Parallel Table of Authorities and Rules - For the Code of Federal Regulations and the
United States Code
❖ Federal Register - Published by the Office of the Federal Register, National Archives
and Records Administration (NARA), the Federal Register is the official daily
publication for rules, proposed rules, and notices of Federal agencies and organizations,
as well as executive orders and other presidential documents
❖ FederalRegister.gov - Unofficial, HTML (XML-based) edition of the daily Federal
Register provided by the Office of the Federal Register, National Archives and Records
Administration
164
❖ Reginfo.gov - Provides reliable, transparent information about regulations under
development

Purple book
Background
The Purple Book is a compendium of FDA-approved biological products and their bio-
similar and interchangeable products. It is similar to the Orange Book, which is a listing of
approved generic drugs with therapeutic equivalency to brand products. Information for each
product listed in the Purple Book includes its BLA tracking number, product name, product
proprietary name, date of licensure, date of first licensure, reference product exclusivity
expiration date, indication as to whether the product is interchangeable (I) or bio-similar
(B), and whether the product was withdrawn from the market.
Evaluations”, the purpose of the purple book is:
1. To assist users, understand if a biological product has been approved by FDA under the
PHS Act with a reference product (already approved biological product)
2. To help identify if there is any exclusivity for a given reference product. The Purple
Book includes two lists of biologics. The first list includes biologics approved by the
FDA’s Center for Drug Evaluation and Research (CDER) and the second list includes
biologics approved by the Center for Bio-logic Evaluation and Research (CBER).
The book also includes the following information about the biologics:
❖ BLA Number
❖ Non-Proprietary Product Names
❖ Proprietary Product Names
❖ Date the Product was approved in the Market
❖ Date of the first Licensure
❖ Whether the Product is Bio-similar or Interchangeable
❖ Reference Product with an Expiry Date
❖ Whether the Product is withdrawn from the Market

165
 APPENDIX A

Practice Question

1. What is Regulatory Affairs?

2. What are the goals of Regulatory Affairs Professionals?
3. What are the Roles of Regulatory Affairs professionals?
4. What is an Investigational New Drug (IND) application?
5. What is a New Drug Application?
6. What is an Abbreviated New Drug Application (ANDA)?
7. What are the different stages of drug discovery?
8. What is the generic drug? Define and explain process of generic drug development.
9. Define clinical trial and explain in brief about different phages of clinical trial.
10. Give the brief overview on regulatory authorities of following-
A. India
B. United state
C. European union
D. Japan
E. Canada
11. What is the procedure for export of pharmaceutical products?
12. Write in detail about-
A. common technical document
B. Electronic common technical document
C. ASEAN common technical document
13. Define following-
A. Institution review board/ independent ethical committee
B. Sponsor
C. Investigators
14. What is orange book?
15. Give detail about code of federal regulation.
16. Write in brief about purple book.

166
 About the Author
Dr. B.E. Wanjari is Principal&Associate Professor in
Gondia College of Pharmacy. Completed his Ph. D.
from Dept. of Pharmaceutical sciences RTMNU
Nagpur and Master of Pharmacy in Pharmaceutics
from RGUHS Banglore. He has 16 years of
experience in teaching and 31 publications in
International Journal, 1 publication in National

Krushnakumar D. Khalode is Assistant Professor,

Department of Pharmaceutical Chemistry in Gondia
College of Pharmacy. He has done his Master of
Pharmacy in Pharmaceutical chemistry from R. T. M.
N.U. and pursuing his Ph. D. from SPV university.
He has two years of Industrial Experience and five
years of Experience in Teaching and has 20

K. R. Bhendarkar is Assistant Professor, Department

of Pharmaceutical Quality Assurance in Gondia
College of Pharmacy. He has completed his Master of
Pharmacy from R. T. M. N. U. University. He has 8
years of Experience in Marketing and has 3 years of
Experience in Teaching and has 6 publications.

M . N. Rangari is Assistant Professor, Department of

Pharmaceutical Chemistry in Gondia College of
Pharmacy. He has done his Master in Pharmaceutical
Chemistry from R. T. M. N.U. University. He has 4
years of experience in teaching and has 8

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